Skip to main content
Download PDF

Immunotherapies in rare cancers

Molecular Cancer volume 22, Article number: 23 (2023) Cite this article

Abstract

Cancer remains a leading cause of death worldwide, placing a significant burden on healthcare systems as well as the global economy. Rare cancers comprise a group of about 200 cancers that individually occur at extremely low frequencies. In the United States (US), their frequency is approximately 15 cases per 100,000 people, and it is even lower in Europe with approximately 6 cases per 100,000 people. However, combined their frequency of occurrence is much higher than any singular cancer. Cancer treatment and management has tremendously improved in the last decade, particularly with the administration of immune-based therapies. The four most prevalent immune-based therapies are (1) the use of immune-checkpoint inhibitors, (2) macrophage therapy, (3) Chimeric Antigen Receptor (CAR) T cell therapy, and (4) neoantigen-based therapies. In our review, we discuss these various aproaches and their implementation in the treatment of a variety of rare cancers. Furthermore, we discuss their limitations and potential strategies to overcome them to enhance the therapeutic efficacy of these approaches. Finally, our article presents the future directions and other additional immune therapies that may be incorporated into the treatment of rare cancers.

Introduction

Cancer is the second leading cause of death globally, including in the US. The American Cancer Society has estimated that about 1.9 million new cases were diagnosed in the U.S. in 2022. The most prevalent cancers amongst men are lung, prostate, and colorectal cancers, while women are commonly afflicted with breast, lung, and colorectal cancer (https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf). Conversely, certain cancers such as Merkel cell cancer, types of hepatobiliary cancers, mesothelioma, and adrenal cancers (amongst others) have low incidences and are categorized as rare cancers. The US National Cancer Institute defines rare cancers as those that have less than 15 cases per 100,000 people each year, while the European Union includes cancers that have less than 6 cases per 100,000 people per year (https://www.cancer.gov/). About 200 different cancers are grouped in this category, and together their incidence is higher than any particular cancer [1]. However, the clinical outcome of these cancers is usually grim. These cancers are difficult to diagnose, and often the cancers are identified only after they have progressed into advanced stages. The lower incidences translate into limited samples (biopsy or surgical tissues, patient-derived cell lines) for preclinical studies and few clinical trials to evaluate new interventions or therapeutic strategies. These facts highlight the importance of studying these cancers and identifying the most effective therapeutic strategies to improve patient outcomes.

The conventional treatments administered for both common [2] and rare cancers (https://www.cancer.gov/) include surgery, chemotherapy, radiotherapy and often a multidisciplinary combination of these treatments. The traditional paradigm of these therapies is to target and eliminate the cancer cells by interfering with tumor cell growth and survival. Unfortunately, this limits the efficacy of these treatments as cancers often escape with the help of acquired mutations and cancer stem cells, leading to relapse. Additionally, these therapies usually generate a multitude of harmful side effects. These issues have brought research and clinical focus to immunotherapies. Similar to other health disorders, the immune system, both innate and adaptive, are activated in response to cancer. The immune system plays key roles in both suppressing and promoting cancers by being involved in all aspects of response to cancer: (a) elimination of cancer cells, (b) maintaining equilibrium between tumor cells and immune cells, and (c) facilitating the growth of tumor cells in an immunocompetent host microenvironment [3]. The increased understanding of our immune system and identification of neoantigens has brought attention to identifying and developing strategies to augment immune responses directed towards elimination of these cancer cells and re-activation of anti-tumor responses with the help of memory cells in the event of cancer relapse. In this review, we discuss the various immune-based therapeutic approaches and their current status in the treatment of rare cancers, their limitations and potential strategies to overcome them, recent advances in the identification of biomarkers, and future directions in immunotherapy for rare cancers.

Immune-based therapeutic approaches and their current status in the treatment of rare cancers

Immune-checkpoint inhibitors

Immune cells express receptors known as immune checkpoints that are involved in the regulation of immune homeostasis, specifically activation of T cells, certain myeloid cells, and regulatory cytokines. Cancer patients have deficient regulatory systems, wherein immune-checkpoint pathways promoting immune-suppressive functions are upregulated and immune-activating pathways are downregulated [4]. In the past decade, immune-checkpoint inhibitors, predominantly monoclonal antibodies, have positively impacted cancer management and treatment, thereby gaining prominence. Immune-checkpoint inhibitors have been reported to generate sustainable responses and are administered in metastatic and more recently in neoadjuvant and adjuvant settings [5]. One immune checkpoint (IC) receptor, CTLA-4, has shown extensive promise as therapeutic target. CTLA-4, a structural homologue of CD28 is a membrane receptor on cytotoxic T cells [6]. Activation of T cells occurs in two steps, the first being the recognition of antigens presented by the MHC and the second being costimulation generated upon binding of CD28 to CD80 or CD86 on the antigen presenting cells. CTLA-4 can bind to CD80 and CD86 with higher affinity than CD28, thereby impeding T cell activation [7]. CTLA-4 is expressed constitutively on T regulatory (Treg) cells as well as on activated effector T cells [8, 9]. Ipilimumab, an antibody that targets CTLA-4, was the first immune-checkpoint inhibitor to receive approval from the U.S. food and drug administration (FDA) in 2011 for use in cancer treatment. This was in melanoma based on the results of clinical trial NCT00094653 [10]. While in melanoma patients, Ipilimumab demonstrated significant benefit with combined data analysis from 12 trials indicating improved 10-year survival, [11], it has had limited success in other cancers [12].

Another immune-checkpoint target is Programmed Cell Death protein 1 (PD1). PD1 is a key immune-checkpoint receptor that is expressed by T cells and mediates immunosuppression. Its ligand is programmed cell death ligand 1 (PDL1), which is expressed by T cells, B cells, and some non-hematopoietic cells. In a normal immune system it regulates T cell function; however tumors utilize this pathway to their benefit by upregulating PDL1 on their surface and binding to the PD1 on T cells [13]. This interaction causes apoptosis of T cells. Thus, targeting the PD/PDL1 pathway is helpful in targeting tumors. The inhibition of this interaction facilitates normal T cell surveillance and the endogenous anti-tumor response can be increased [14]. Many PD1 inhibitors including nivolumab, pembrolizumab, and cemiplimab, as well as PDL1 inhibitors such as atezolizumab, avelumab, and durvalumab have been approved in recent years [15]. They have shown to be effective and safe for treating melanoma, renal cell carcinoma, and non-small cell lung cancer (NSLC) [16].

Based on the success of immune-check point inhibitors, there are several completed and ongoing clinical trials demonstrating the efficacy of these inhibitors in treating rare cancers. These are summarized in Table 1. Overall, although the use of checkpoint inhibitors is not yet mainstream for rare cancers, there have been several trials reporting their efficacy. Recently, much attention has been turned to different rare malignancies, including non-melanoma cutaneous cancers (including the much less common Merkel cell cancer), hepatobiliary cancers, endocrine and adrenal cancers, and mesothelioma. Active clinical trials are also included in the next paragraphs of this section. For all rare cancers as defined by the National Cancer Institute, a large phase 2 study intending to enroll over 800 patients, is ongoing (NCT02834013 Nivolumab and Ipilimumab in Treating Patients with Rare Tumors). This study investigates nivolumab and ipilimumab in treating patients with rare tumors. For the purposes of this review, however, we focus on the rare solid cancers that have recent clinical trial data within the last decade.

Table 1 Ongoing Clinical Studies in Rare Tumors utilizing Immune-checkpoint inhibitors
Full size table

Kaufman et al [17] performed a phase 2 trial of avelumab (anti-PD1 antibody) in patients with metastatic Merkel cell cancer who had failed chemotherapy. An overall response rate of 31.8% was reported, with minimal risk of adverse events (6%). Nghiem et al [41] reported an even higher response rate of 56% is a similar population of advanced Merkel cell cancer patients. Interestingly, responses were observed in both patients with Merkel-cell polyomavirus (MCPyV) positive tumors and negative tumors, suggesting a common immune pathway between both subtypes of Merkel cell cancer. The potential role of checkpoint blockade in the adjuvant setting is actively being investigated in several clinical trials as well, including NCT04291885 Immunotherapy Adjuvant Trial in Patients with Stage I-III Merkel Cell Carcinoma (I-MAT), NCT03271372 Adjuvant Avelumab in Merkel Cell Cancer (ADAM), NCT03798639 Nivolumab and Radiation Therapy or Ipilimumab as Adjuvant Therapy in Treating Patients with Merkel Cell Cancer, and NCT03712605 Testing Pembrolizumab versus Observation in Patients with Merkel Cell Carcinoma After Surgery, STAMP Study. Due to the aggressive nature of Merkel cancer and the failure of distant disease control often leading to patient mortality, these new trials offer new adjuvant treatment for this rare but highly morbid cancer. Other studies for non-melanoma skin cancers are also listed in Table 1, including the more common squamous cell cancer.

Hepatobiliary cancers are often very morbid cancers with limited treatment options, and as such, many investigators have tested checkpoint blockade in these patients in the hopes that durable responses can be achieved. A recent meta-analysis analyzing this pathway for hepatocellular carcinoma showed that a high expression of PDL1 was significantly associated with a poor overall survival rate, which demonstrates the pathway’s prominent role in tumor progression [42]. However, current therapeutic studies are limited, and the results of these studies have not been very promising, as shown in Table 1. Overall, the numbers of patients in these studies have been relatively low with limited follow-up, low complete response rates, and modest benefits over standard over care (e.g., chemotherapy or targeted therapy). One of more recent studies by Kelley et al [22] tested the combination of tremelimumab (anti-CTLA4) with durvalumab (anti-PD1) compared to durvalumab alone or sorafenib (as standard of care). Compared to sorafenib, durvalumab alone or in combination with tremelimumab resulted in an increase in median OS of about 2–3 months (median OS 16.43 months, 95% CI 14.16 to 19.58) with tremelimumab and durvalumab and 16.56 months (95% CI, 14.06 to 19.12) with durvalumab alone, compared to 13.77 months (95% CI, 12.25 to 16.13) with sorafenib. It is thought that the immunologically “cold” microenvironment of hepatobiliary tumors contributes to relatively poor responses to immunotherapy [43, 44]. Active clinical trials seek to combine immunotherapy with ablative techniques in order to produce antigen targets for immunotherapy and may hold promise for future discovery. These include NCT03101475 Synergism of Immunomodulation and Tumor Ablation (ILOC), NCT03937830 Combined Treatment of Durvalumab, Bevacizumab, Tremelimumab and Transarterial Chemoembolization (TACE) in Subjects with Hepatocellular Carcinoma or Biliary Tract Carcinoma, NCT04605731 Durvalumab and Tremelimumab after Radioembolization for the Treatment of Unresectable, Locally Advanced Liver Cancer, NCT05301842 Evaluate Durvalumab and Tremelimumab +/− Lenvatinib in Combination with TACE in Patients with Locoregional HCC (EMERALD-3), and NCT04522544 Durvalumab (MEDI4736) and Tremelimumab in Combination With Either Y-90 SIRT or TACE for Intermediate Stage HCC With Pick-the-winner Design.

Another rare solid cancer for which there has been recent progress with immunotherapy is adrenal tumors. Like hepatobiliary cancers, adrenal cortical carcinoma (ACC) is associated with a dismal prognosis, and there are limited viable treatment options. Naing et al [19] and Klein et al [31] reported modest efficacy of single agent (pembrolizumab) or dual agent (nivolumab and ipilimumab), respectively, for patients with advanced ACC. These trials had small cohorts of 15 or less patients. Within the study by Naing et al, the investigators reported similarly modest results for adrenal pheochromocytomas or paragangliomas (as shown in Table 1). As one of the rarest cancers, few active clinical trials are investigating immunotherapy for ACC, and these include NCT00457587 Preclinical Study Towards an Immunotherapy in Adrenocortical Carcinoma and NCT02673333 Single Agent Pembrolizumab in Subjects with Advanced Adrenocortical Carcinoma.

Lastly, immunotherapy has recently been approved as first-line therapy for pleural malignant mesothelioma. Early trials in the mid to late 2010s showed modest response rates to tremelimumab [33, 34]. However, larger randomized clinical trials in published in the 2020s showed superior benefit with other checkpoint inhibitors. CheckMate 743 randomized patients to nivolumab plus ipilimumab versus traditional chemotherapy with cisplatin and pemetrexed. All outcomes were improved with immunotherapy compared to chemotherapy, with an increase in 3-year OS rates (23% versus 15%) and 3-year PFS (14% versus 1%) [38]. Similarly, PrE0505, which was a phase 2, single-arm, multicenter study, enrolled patients with previously untreated pleural mesothelioma reported an 8-month OS benefit with durvalumab plus cisplatin and pemetrexed compared to historical chemotherapy only controls [37]. While the majority of studies with mesothelioma have been performed for pleural-based disease, its use is being investigated in the less common peritoneal mesothelioma. Raghav et al [39] recently published their small cohort of 20 patients with peritoneal mesothelioma treated with atezolizumab in combination with bevacizumab, achieving an OR of 40%, 1-year PFS of 61%, and 1-year OS of 85%. Intuitively, the biology of peritoneal mesothelioma may behave similarly to pleural mesothelioma, so these latest results are encouraging for the rarer peritoneal-based disease. Ongoing clinical trials in peritoneal mesothelioma may contribute to the growing body of evidence that immunotherapy may be effective for this site of disease as it is for pleural-based disease. These trials include NCT05001880 Chemotherapy with or without Immunotherapy for Peritoneal Mesothelioma and NCT05041062 A Study of Immunotherapy Drugs Nivolumab and Ipilimumab in Patients with Resectable Malignant Peritoneal Mesothelioma.

In summary, the clinical application and utility of immunotherapy for rare cancers has been mixed in recent years, with significant improvement in outcomes for certain cancers (Merkel cell carcinoma and pleural/peritoneal mesothelioma), but less encouraging for others (hepatobiliary cancers and endocrine/adrenal malignancies). The biology and microenvironment as well as tumor vessel heterogeneity among the distinct types of tumors may account for differences in response among solid tumors [45]. Ongoing and future studies that combine immunotherapy with other treatment modalities (including the clinical trials listed throughout this section) may become a valid option for treatment-refractory patients with rare cancers. The CRAFT trial is one example of how individualized targeted therapy combined with immunotherapy (anti-PDL1) may augment responses by addressing both actionable genetic targets and the tumor immune microenvironment [46]. Innovative clinical trials such as these may achieve higher and more durable responses for patients with rare cancers, and the results of these trials are eagerly awaited.

Macrophage therapy

In recent years, a new form of immunotherapy targeting and modulating macrophages has been investigated. Macrophages (Fig. 1) are specialized to their host tissues and perform a variety of functions, including ingesting and degrading dead cells and debris, eliminating pathogens, and regulating inflammatory responses [47]. Traditionally, there are two categories of macrophages, the classically activated macrophages (M1) and the alternatively activated macrophages (M2). M1 macrophages promote inflammatory responses by secreting cytokines such as TNFα, IL1-B, and IL12 to enhance the recruitment of Th1 T cells to the site of inflammation [48]. Additionally, they upregulate genes and other co-stimulatory molecules that enhance T cell response(s), which serve a critical anti-tumor role [49]. On the other hand, M2 macrophages have a role in normal immune function and homeostasis, such as stimulating Th2 cells, eliminating parasites, wound healing, immune regulation, and tissue regeneration as well as the maintenance of the tumor microenvironment (TME) [50].

Fig. 1
figure 1

The role of macrophages in tumor growth and progression. Macrophages are involved in several processes associated with tumor growth and progression, including inflammation, immune regulation, angiogenesis, invasion, and metastasis in the solid tumor microenvironment. Each subtype of macrophage is characterized by the expression of specific cytokines, chemokines, and toll-like receptors

Full size image

Like other immune cells, macrophages are found in cancer tissues as well. These are known as tumor-associated macrophages (TAMs). The TAM pool is generated through both monocyte recruitment and through the local/tissue resident macrophage proliferation [51]. The phenotype of TAMs is similar to that of M2 macrophages. They promote tumor progression through increased gene instability, angiogenesis, fibrosis, immunosuppression, lymphocyte exclusion, invasion, and metastasis. Furthermore, they suppress the anti-tumor immunity by inhibiting normal T cell function, including both cytotoxic T cells and Treg cells [52]. TAMs are known to support angiogenesis in two ways – first by promoting angiogenesis initiation in avascular areas and second by helping in the vascular flow through the remodeling of the vasculature [53]. TAMs have been reported to support metastasis by facilitating tumor cell invasion and migration [54]. Thus, macrophages-based immunotherapy has become an increasingly viable option.

Genetically engineered macrophages (GEM) are one platform of macrophages-based immunotherapy. Macrophages can be engineered to modulate the tumor microenvironment to a more anti-tumor one. They can be engineered to secrete proteins like soluble TGF beta-receptor II or interleukin 21 to decrease immune suppression or activate immune cells, respectively. Conversely, they can be engineered to prevent macrophage mediated immune suppression by knocking out the genes involved in the deregulation of cytotoxic cells like PDL1 and interleukin 10 with the help of CRISPR technology [55]. Preclinical data in glioblastoma (GBM) showed promising results with no increased risk to morbidity in animals or increased tumor growth [55]. The encouraging data from these studies warrant further investigation to extend this approach into clinical settings.

Another approach to modulate TAMs is to impair their functioning through antibodies that target proteins expressed on TAMs. Data from a phase I clinical study in 63 diffuse type tenosynovial giant cell tumor patients treated with emactuzumab showed favorable responses. Biopsy tissues were available for 36 patients, and these demonstrated a significant decrease in CSF1R+ and CD68/CD163+ macrophages. Independently the overall objective response rate (ORR) was high at 71%. Additionally, the responses were durable with an ORR of 70 and 64% after one and 2 years post enrollment into the study, respectively [56].

A third approach to macrophage modulation, chimeric antigen receptor (CAR)-T cell-mediated TAM modulation was recently described in an ovarian cancer pre-clinical model. The authors used CAR-T cells to selectively delete folate receptor β expressing (FRβ+) TAMs in syngeneic tumor mouse model. This resulted in the enrichment of pro-inflammatory monocytes, increase in tumor-specific CD8+ T cells, slowed tumor progression and increased survival [57]. This is an exciting, innovative approach to modulate macrophages using CAR-T cells.

Macrophages have the ability to penetrate and survive within the tumor tissues. Based on this, University of Pennsylvania researchers recently described a new macrophage-based therapy. This is an individualized approach where monocytes are isolated from the patient’s blood, modified with the desired antigen-specific chimeric receptor, and then given back to patients [58]. The FDA recently granted Fast Track designation to a CAR-M, CT-0508, a human epidermal growth factor receptor 2 (HER2) targeted chimeric antigen receptor macrophage for the treatment of patients with solid tumors (https://carismatx.com/carisma-therapeutics-announces-u-s-food-and-drug-administration-grants-fast-track-designation-to-ct-0508-for-the-treatment-of-patients-with-solid-tumors/). This approach, if successful, would be extremely beneficial to other cancers, particularly those in which tumor microenvironment limits the efficacy.

Chimeric antigen receptor (CAR) T cell therapy

CAR-T cell therapy is a more contemporary form of immunotherapy. T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various stimulatory molecules. Upon administration, these modified T cells traffic to and recognize cancer cells in an HLA-independent manner. T cells expressing CARs have been propelled to the forefront of experimental cell therapies due to their clinical success for hematological malignancies targeting CD22, CD30, and CD-19–expressing B-cell acute lymphocytic leukemia [59,60,61,62,63]. Earlier this year (2022), the US FDA approved CAR-T cell therapies for certain rare cancers, including follicular lymphoma, B-cell non-Hodgkin lymphoma, B-cell acute lymphoblastic leukemia, and Mantle Cell lymphoma [64]. While these developments show tremendous promise in this form of therapy, it is important to note that CAR-T cell therapies for solid tumors have shown limited anti-tumor activity in early phase clinical testing despite targeting a variety of target antigens and tumor types [65,66,67,68,69,70]. A study in ovarian cancer model demonstrated an RNA vaccine-based approach of increasing the efficiency of CAR-T cells in solid tumors and utilized protein claudin 6 (CLDN6) as the CAR target. CLDN6 is a tight junction that is regulated developmentally. This study showed that delivery of CAR antigens using nanoparticulate RNA vaccine into the lymphoid compartments stimulated the adoptively transferred CAR-T cells. This system promoted the selective expansion of CAR-T cells and tumor regression was achieved at subtherapeutic doses of the CAR-T cell [71]. A phase I/IIa, FIH, open-label, multicenter, clinical trial (NCT04503278) is evaluating the safety and efficacy of CLDN6 CAR-T with or without CLDN6 RNA-LPX in patients with CLDN6-positive relapsed or refractory advanced solid tumor. In Table 2, we have summarized on-going clinical trials evaluating the efficacy of CAR-T cell therapy in rare cancers.

Table 2 Ongoing Clinical Studies in Solid Tumors utilizing CAR T-cell therapy
Full size table

CAR-T cells require trafficking to the tumor cell surface so that they may bind to the target molecule (main targets include immune checkpoints, chemokine-receptor network, tumor vasculature, and immune suppressive cells and cytokines, as shown in Fig. 2B-F). However, the tumor microenvironment impedes this transit. Solid tumors produce chemokines like CXCL1, CXCL12, and CXCL5 within the tumor microenvironment, preventing the T cells from reaching the tumor cells. For example, a study in pancreatic cancer (PC) model, reported that carcinoma-associated fibroblasts (CAF) that expressed fibroblast activation protein (FAP) produced CXCL12. The study showed that the T cell population was less abundant in the regions where FAP+ cells were present, suggesting a link between CXCL 12 expression and T cells [72]. Another study in prostate cancer model showed that CXCL5 secreted by the tumor recruited CXCR2-expressing myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment. This resulted in the secretion of cytokines and enzymes that suppressed the proliferation and the activation of the local T cells [73]. The findings from these relatively common tumor models (PC and prostate) are important as they could be extended to identify potential biomarkers as well further challenges and opportunities in translating CAR-T therapy into the clinic for rare cancers.

Fig. 2
figure 2

CAR-T cells mediating their anti-tumor effects. CAR-T cells require trafficking to the tumor cell surface so that they may bind to the target molecule to mediate anti-tumor effects. The main targets include immune checkpoints, chemokine-receptor network, tumor vasculature, and immune suppressive cells and cytokines (Fig. 2B-F)

Full size image

Collectively, the data thus far indicate that CAR-T therapy is effective for treating certain rare cancers and its efficacy for some more is currently being evaluated through clinical trials. The identification of biomarkers to predict the sensitivity of the tumor to this therapy, and other molecules whose concurrent therapeutic targeting can enhance the clinical outcome of CAR-T cell therapy would quicken the development of this therapy for a broader range of tumors.

Neoantigen-based therapies

Neoantigens are tumor-cell specific proteins resulting from mutations in the protein-coding regions of DNA through acquired mutations, alternative splicing and gene rearrangement [74]. Additionally, in most human tumors without a viral aetiology, tumor neoantigens could emanate from an assortment of non-synonymous genetic alterations, including single-nucleotide variants, insertions and deletions, gene fusions, frameshift mutations, and structural variants [75, 76]. Furthermore, cancer-specific mutations often generate neoepitopes which are present on the surface of cancer cells by MHCs. Notably, these may also function as neoantigens [77].Tumor-specific antigen (neoantigen) are usually located on the outer surface of tumor cell and are particularly identified by neoantigen-specific T cell receptors with the help of histocompatibility complexes (MHCs) molecules [75, 76, 78,79,80]. Some neoantigens enhance therapeutic efficacy and could potentially serve as biomarkers to predict patient response to cancer immunotherapy [78, 81]. Recent literature indicate that neoantigens play a pivotal role in tumor-specific T cell-mediated anti-tumor immunity [79, 80, 82]. Some investigations indicate that neoantigen-targeting approaches can generate strong and durable anti-tumor immune reactions in individual tumor microenvironments. The main neoantigen-based tumor therapies include long synthetic peptide (SLP) vaccines, DNA/mRNA vaccines, dendritic cell-based vaccines, neoantigen-specific T cell receptor-based therapies, and bispecific antibodies associated with public neoantigens. Recent studies have demonstrated the effectiveness and feasibility of neoantigen-targeted cancer vaccines on murine tumor models including oesophagal squamous cell carcinoma [83], glioma [84], and sarcoma [85]. Some of the neoantigen based therapeutic approaches are discussed below.

Neoantigen-based adoptive cell therapy (ACT)

This therapy aims at stimulating the patients’ immune response(s) by transferring neoantigen-targeting lymphocytes into the patients. Some studies have reported that the tumor-infiltrating lymphocytes (TILs) in the patients recognize neoepitopes expressed by the patient’s own tumor, underscoring the biological relevance of this therapy. For example, a study reported that adoptive transfer of CD4+ T helper 1 (Th1) cells that recognized a mutation expressed by the tumor cells could mediate the regression of metastatic cholangiocarcinoma [86]. Tran and colleagues [87] reported that in a cohort of 10 patients with metastatic gastrointestinal (GI) cancer, 9 had CD4+ and/or CD8+ TILs that recognized one to three neoepitopes generated by somatic mutations in the patients’ tumors. Additionally, they reported that these epitopes were unique to the individual patients. However, one of the patients expressed a human leukocyte antigen T cell receptor from CD8+ TILs that targeted the KRASG12D [87]. Similarly, Cafri and colleagues [88] reported the presence of CD4+, and CD8+ memory T cells that targeted oncogenic KRAS in the peripheral blood of 3/6 metastatic colon cancer patients. Oncogenic KRAS mutations are common in several cancers including GI. Theoretically, expanding or generating these CD8+ TILs that target the mutant KRAS and using them for therapy would lead to the development of personalized therapies for a broad spectrum of patients who have tumors with oncogenic KRAS.

Recent studies have identified neoantigen-specific CD8+ and CD4+ lymphocytes in patients with relatively low tumor mutation burden cancers such as ovarian (naïve; no prior immunotherapy) [89] and gastrointestinal cancers [88, 90]. The identification of neoepitopes directly in the patient samples brings us closer to clinical application by eliminating the developmental processes such as neoantigen prediction and experimental validation; and increases the chances of therapeutic success. Collectively, these findings indicate that neoantigen-specific lymphocytes could be developed as a personalized therapy for cancer.

Neoantigen-based vaccines

This is another approach targeting neoantigens in the tumors. Three types of neoantigen-targeting vaccines such as nucleic acid (RNA, DNA) – based, synthetic and dendritic cell (DC) based (Fig. 3) are being evaluted for potential use in clinical settings. A phase 1 clinical study, NCT03313778, examined the neoantigen-based lipid-encapsulated vaccine mRNA-4157 in patient with solid tumors including bladder urothelial carcinoma and human papillomavirus-negative head and neck squamous cell carcinoma along with a few common cancer types. Out of 79 individuals treated with mRNA-4157, 16 were treated as a single treatment and 63 were administered mRNA-4157 with the immune checkpoint inhibitor pembrolizumab. mRNA-4157 was safe and well tolerated. Furthermore, these RNA/DNA based vaccines can be administered through encapsulation by delivery vehicles such as lipid nanoparticles (LNPs) or even orally [91]. These studies suggest that RNA/DNA based vaccines hold tremendous potential for therapeutic use.

Fig. 3
figure 3

The different type of vaccines being evaluated for cancer immunotherapy. Three major types of vaccines being evaluated for therapeutic targeting are nucleic acid, dendritic cell and peptide based

Full size image

Neoantigen based peptide vaccines are yet another form of immune therapy. An effective vaccine would induce a significant T cell response that would effeciently target the tumor cells. Additionally, the CD8+ memory T cells need to be activated for a sustainable respone, in case the cancer relaspses. Emerging data have encouraging data. A a phase 2 study assessed the clinical efficacy of synthetic long-peptide vaccine against the HPV-16 oncoproteins E6 and E7 in women with HPV-16–positive, grade 3 vulvar intraepithelial neoplasia. The patients were vaccinated three to four times. It was reported that the vaccine generated T cell responses in all patients; those who had a complete response in 3 months had a considerably stronger interferon-γ–related CD4+ T cell proliferative and a broader CD8+ interferon-γ T cell response than patients who did not have a complete response. Three months post the last vaccination, 60% patients had a favorable clinical response consisting of complete regression was seen in five women and in four of them HPV was undetectable. Twelve months post the vaccination, clinical response was reported in 79% of the patients with complete responses in 9 out of 19 patients. Additionally, at the 24-month folow up, the complete response rate was still maintained [92].

Limitations of these immune therapies and potential strategies to overcome them

Immunotherapeutic approaches have undoubtedly significantly improved cancer management and patient outcomes. However, these approaches have some limitations, on pre-clinical, clinical, economic, and social fronts.

A major roadblock in identifying, developing, and evaluating therapies particularly for rare cancers is that only limited samples are available (https://www.cancer.gov/). The incidence of these cancers is low, thereby the tissue samples to assess biomarkers; patient-derived cell lines and xenograft models to research to study underlying mechanisms as well as the ability to conduct clinical trials is very restricted. An article recently proposed building patient-derived rare cancer models by establishing positive collaborations between multiple clinical and research organizations [1]. The success of such a model would theoretically tremendously benefit and accelerate the identification of biomarkers and drugs for the rare cancers. Of note, immunotherapies have heterogeneous therapeutic outcomes with the responses generated being considerably varied between different individuals. Hence, the data generated with the help of such models might be helpful only for a portion of the patients. Identification of reliable biomarkers would likely strengthen these predictions and possibly help identify or streamline the population that would either benefit or be non-responders to these therapies.

In the clinical settings, the challenges are similar to conventional cancer therapies. Several patients acquire resistance to IC inhibitors, due to which the disease eventually progresses. Compounding this issue is the fact that the acquisition of resistance is varied amongst different tumor types and thereby has not yet been characterized. In addition to the samples available for examination, there are limitations to tools available for analyses, respectively. Moreover, a uniform guideline needs to be adopted for defining acquired resistance to immunotherapy [93]. Further insight into the underlying mechanisms of acquired resistance is necessary to improve the therapeutic efficacy of current checkpoint inhibitors as well as for developing next generation of improvised inhibitors. One potential strategy to overcome this resistance or improving their therapeutic efficiency would be combining immune checkpoint inhibitors with either conventional therapies or concurrently administering two or more checkpoint inhibitors. T cell exhaustion is another limitation in the clinic. Clinical data indicated that PD1 and T cell Ig and ITIM domain (TIGIT) inhibitors regulated the expansion and function of tumor antigen-specific CD8+ T cell in melanoma patients [94], indicating that combining multiple checkpoint inhibitors could be a viable approach to prevent T cell exhaustion. Emerging studies show that this strategy could benefit certain rare cancers such as ovarian [95] and colorectal cancer [96].

Metabolic pathways are another attribute that can limit the efficacy of several immune-based approaches. The majority of these approaches including checkpoint inhibition, adoptive T cell therapies and oncolytic virus mediate anti-tumor responses through effector T cell responses. Many of the tumor microenvironment conditions such as low pH, reduced nutrient availability, presence of suppressive metabolites and hypoxia can impair the functioning of T cells. A recent review article beautifully summarized how the metabolic barriers impede various immunotherapeutic strategies [97].

Sterner and colleagues [98] presented a comprehensive review article on the challenges faced by CAR-T cell therapy and approaches to overcome them. In brief, one concern about the therapy is that antigens often escape. This possibly could be overcome by building dual or tandem CAR, thereby targeting multiple antigens. This strategy has shown promising results in certain cancers such as multiple myeloma [99] and B cell malignancies [100]. Another issue is restricted CAR-T cell trafficking and limited tumor infiltration. These issues could be overcome by regional delivery of the CAR-T cells. This has been successful in certain preclinical models such as mesothelin cancer [101]. CAR-T cell trafficking was demonstrated to be enhanced by through the overexpression of CXCR1/CXCR2 [102, 103]. Approaches being evaluated with the aim of improving its effectiveness in an immune-suppressed environment including combing it with PD1 inhibition [104, 105], and modulating them to secrete immunostimulatory signals like IL-12 [106] and Il-15 [107] and reducing the effects of immunosuppressive cytokines like IL-4 [108]. The other major concern surrounding this approach is the associated toxicity. CAR with modified binding affinities of scFv component [109], reduced cytokine secreting potential: CD19; B cell lymphoma [110] and genetically modified CAR: CRISPR/CAS9 mediated granulocyte macrophage colony-stimulating factor (GM-CSF) knockout CAR are being evaluated and have shown promising results in preclinical and early phase clinical trials. Further studies and clinical trials are needed to optimize and bring these approaches to clinical use for both, common and rare cancers.

Another deterrent to immune-based therapies are the high-costs associated with them. Unfortunately, not all patients who could benefit from them are able to afford them and not all costs are covered by health insurances. Similarly, receiving such advanced therapies requires consistent access to an experienced healthcare team and establishments that may be unavailable or limited in many countries with low and middle and income. Thus, based on the facts that only select individuals will benefit from these therapies and the expense and logistics associated with them, many patients either voluntarily or due to the economic burden restrict to only conventional therapies. It will be important to develop alternate approaches like biosimilars and vaccines that would be more cost-effective and globally be more accessible.

Together, these studies and reports indicate that while there are limitations to the current immune-based treatment regimes, the shortcomings have been identified and research efforts are being directed at overcoming them and improving patient outcomes.

Conclusions and future directions

As more is discovered regarding the multiple mechanisms of action and resistance behind the various immune-based therapeutic strategies, immune therapies may become more personalized. Mechanistic details being described for these strategies are likely to help develop both improved therapeutic agents and strategies that would overcome the shortcomings of the current approaches. Combination therapies with immune therapy will likely continue to grow in the future.

For rare cancers, one form of combination therapy will continue to be administration of two variations of the same treatment, for instance two immune-checkpoint inhibitors. Some completed and some ongoing clinical trials have reported increased efficacy in treating tumors with this approach. For example as discussed in section 2.1, the combination therapy of nivolumab and ipilimumab showed significant efficacy in patients with recurrent malignant pleural mesothelioma in phase III trial, supporting its administration as the first-line of therapy [38]. Similarly, the combination therapy of nivolumab and ipilimumab has been reported to have higher efficacy than single agent nivolumab in treating sarcoma patients [40] and some biliary tract cancer patients [30]. In hepatocellular carcinoma, the combination of atezolizumab and bevacizumab generated better patient outcomes than sorafenib alone [26]. Additionally, such combinations may potentially be helpful in re-sensitizing refractory tumors. Conversely, preliminary data from some trials suggest that certain combinations could be toxic to the patients. The results from IMMUNOBIL PRODIGE 57 trial indicated that concurrent administration of paclitaxel with anti-PDL1 and anti-CTLA4 resulted in a high rate of anaphylaxis compared to the combination of taxane without anti-CTLA4 in patients with biliary tract tumors [28]. Such information is also of high value as it helps design combinations that would maximize the patient benefits and re-evaluate combinations that would be toxic.

Another combination approach is to add one form of immunotherapy to either conventional therapies or to combine multiple forms of immunotherapies together. The results from a phase II trial administering durvalumab during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma showed promising results, supporting further trials [35]. An example of combining multiple forms of immune based approaches is the CD19-TriCAR-T therapy. This approach concurrently targets CD19 Positive Non-Hodgkin Lymphoma cells, inhibits PD-L1 signaling, and stimulates the activation and expansion of T/NK cells. CD19-TriCAR-T therapy is being evaluated in phase I (NCT03720496) and II (NCT03497533) trials [111, 112]. The success of such therapeutic strategies would potentially hold tremendous benefits. In addition to them being more effective than single agents, it theoretically would be less time consuming and more cost effective, which are also important in the management of many rare cancers.

Availability of data and materials

Not applicable.

Abbreviations

CAR-T cells:

Chimeric Antigen Receptor (CAR) T cell

IC:

Immune checkpoint

(Treg) cells:

T regulatory

PD1:

Programmed Cell Death protein 1

PDL1:

Programmed cell death ligand 1

CAF:

Carcinoma-associated fibroblasts

HER2:

Human epidermal growth factor receptor 2

MDSCs:

Myeloid-derived suppressor cells

TIGIT:

Ig and ITIM domain

TAMs:

Tumor-associated macrophages

GEM:

Genetically engineered macrophages

IFN-γ:

Mouse interferon-gamma

CLDN6:

Protein claudin 6

DC:

Dendritic cell

PFS:

Progression-free survival

LNPs:

Lipid nanoparticles

ICB:

Immune checkpoint blockade ()

GM-CSF:

Granulocyte macrophage colony-stimulating factor

CRISPR:

Clustered Regularly Interspaced Short Palindromic Repeats

Cas9:

CRISPR-associated (Cas) endonuclease

References

  1. Kondo T. Current status and future outlook for patient-derived cancer models from a rare cancer research perspective. Cancer Sci. 2021;112(3):953–61.

    Article  CAS  Google Scholar 

  2. Tannock IF. Conventional cancer therapy: promise broken or promise delayed? Lancet. 1998;351(Suppl 2):SII9–16.

    Article  Google Scholar 

  3. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70.

    Article  CAS  Google Scholar 

  4. Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50(12):1–11.

    Article  Google Scholar 

  5. Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022;19(4):254–67.

    Article  Google Scholar 

  6. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174(3):561–9.

    Article  CAS  Google Scholar 

  7. Dyck L, Mills KHG. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol. 2017;47(5):765–79.

    Article  CAS  Google Scholar 

  8. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192(2):303–10.

    Article  CAS  Google Scholar 

  9. Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. 2001;1(3):220–8.

    Article  CAS  Google Scholar 

  10. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  CAS  Google Scholar 

  11. Ribas A, Flaherty KT. Gauging THE LONG-TERM BENEFITs of Ipilimumab in Melanoma. J Clin Oncol. 2015;33(17):1865–6.

    Article  Google Scholar 

  12. Alme AK, Karir BS, Faltas BM, Drake CG. Blocking immune checkpoints in prostate, kidney, and urothelial cancer: an overview. Urol Oncol. 2016;34(4):171–81.

    Article  CAS  Google Scholar 

  13. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    Article  CAS  Google Scholar 

  14. Liu J, Chen Z, Li Y, Zhao W, Wu J, Zhang Z. PD-1/PD-L1 checkpoint inhibitors in tumor immunotherapy. Front Pharmacol. 2021;12:731798.

    Article  CAS  Google Scholar 

  15. Chang E, Pelosof L, Lemery S, Gong Y, Goldberg KB, Farrell AT, et al. Systematic review of PD-1/PD-L1 inhibitors in oncology: from personalized medicine to public health. Oncologist. 2021;26(10):e1786–99.

    Article  CAS  Google Scholar 

  16. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  CAS  Google Scholar 

  17. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374–85.

    Article  CAS  Google Scholar 

  18. Nghiem P, Bhatia S, Lipson EJ, Sharfman WH, Kudchadkar RR, Brohl AS, et al. Durable tumor regression and overall survival in patients with advanced merkel cell carcinoma receiving Pembrolizumab as first-line therapy. J Clin Oncol. 2019;37(9):693–702.

    Article  CAS  Google Scholar 

  19. Naing A, Meric-Bernstam F, Stephen B, Karp DD, Hajjar J, Rodon Ahnert J, et al. Phase 2 study of pembrolizumab in patients with advanced rare cancers. J Immunother Cancer. 2020;8(1). https://pubmed.ncbi.nlm.nih.gov/32188704/.

  20. Maubec E, Boubaya M, Petrow P, Beylot-Barry M, Basset-Seguin N, Deschamps L, et al. Phase II study of Pembrolizumab as first-line, single-drug therapy for patients with unresectable cutaneous squamous cell carcinomas. J Clin Oncol. 2020;38(26):3051–61.

    Article  Google Scholar 

  21. Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 Blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379(4):341–51.

    Article  CAS  Google Scholar 

  22. Kelley RK, Sangro B, Harris W, Ikeda M, Okusaka T, Kang YK, et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase i/ii study. J Clin Oncol. 2021;39(27):2991–3001.

    Article  CAS  Google Scholar 

  23. Feun LG, Li YY, Wu C, Wangpaichitr M, Jones PD, Richman SP, et al. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Cancer. 2019;125(20):3603–14.

    Article  CAS  Google Scholar 

  24. Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8.

    Article  CAS  Google Scholar 

  25. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–52.

    Article  Google Scholar 

  26. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905.

    Article  CAS  Google Scholar 

  27. Feng K, Liu Y, Zhao Y, Yang Q, Dong L, Liu J, et al. Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study. J Immunother Cancer. 2020;8(1). https://pubmed.ncbi.nlm.nih.gov/32487569/.

  28. Boileve A, Hilmi M, Gougis P, Cohen R, Rousseau B, Blanc JF, et al. Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. Eur J Cancer. 2021;143:55–63.

    Article  CAS  Google Scholar 

  29. Kim RD, Chung V, Alese OB, El-Rayes BF, Li D, Al-Toubah TE, et al. A Phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 2020;6(6):888–94.

    Article  Google Scholar 

  30. Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M, et al. Evaluation of combination Nivolumab and Ipilimumab immunotherapy in patients with advanced biliary tract cancers: subgroup analysis of a phase 2 nonrandomized clinical trial. JAMA Oncol. 2020;6(9):1405–9.

    Article  Google Scholar 

  31. Klein O, Senko C, Carlino MS, Markman B, Jackett L, Gao B, et al. Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538. Oncoimmunology. 2021;10(1):1908771.

    Article  Google Scholar 

  32. Disselhorst MJ, Quispel-Janssen J, Lalezari F, Monkhorst K, de Vries JF, van der Noort V, et al. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir Med. 2019;7(3):260–70.

    Article  CAS  Google Scholar 

  33. Maio M, Scherpereel A, Calabro L, Aerts J, Perez SC, Bearz A, et al. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol. 2017;18(9):1261–73.

    Article  CAS  Google Scholar 

  34. Calabro L, Morra A, Fonsatti E, Cutaia O, Fazio C, Annesi D, et al. Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. Lancet Respir Med. 2015;3(4):301–9.

    Article  CAS  Google Scholar 

  35. Nowak AK, Lesterhuis WJ, Kok PS, Brown C, Hughes BG, Karikios DJ, et al. Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in. Lancet Oncol. 2020;21(9):1213–23.

    Article  CAS  Google Scholar 

  36. Yap TA, Nakagawa K, Fujimoto N, Kuribayashi K, Guren TK, Calabro L, et al. Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study. Lancet Respir Med. 2021;9(6):613–21.

    Article  CAS  Google Scholar 

  37. Forde PM, Anagnostou V, Sun Z, Dahlberg SE, Kindler HL, Niknafs N, et al. Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial. Nat Med. 2021;27(11):1910–20.

    Article  CAS  Google Scholar 

  38. Peters S, Scherpereel A, Cornelissen R, Oulkhouir Y, Greillier L, Kaplan MA, et al. First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann Oncol. 2022;33(5):488–99.

    Article  CAS  Google Scholar 

  39. Raghav K, Liu S, Overman MJ, Willett AF, Knafl M, Fu SC, et al. Efficacy, safety, and biomarker analysis of combined PD-L1 (Atezolizumab) and VEGF (Bevacizumab) blockade in advanced malignant peritoneal mesothelioma. Cancer Discov. 2021;11(11):2738–47.

    Article  CAS  Google Scholar 

  40. D'Angelo SP, Mahoney MR, Van Tine BA, Atkins J, Milhem MM, Jahagirdar BN, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018;19(3):416–26.

    Article  CAS  Google Scholar 

  41. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, et al. PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma. N Engl J Med. 2016;374(26):2542–52.

    Article  CAS  Google Scholar 

  42. Li XS, Li JW, Li H, Jiang T. Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis. Biosci Rep. 2020;40(4). https://pubmed.ncbi.nlm.nih.gov/32255189/.

  43. Li D, Lin S, Hong J, Ho M. Immunotherapy for hepatobiliary cancers: Emerging targets and translational advances. Adv Cancer Res. 2022;156:415–49.

    Article  Google Scholar 

  44. Ruff SM, Shannon AH, Pawlik TM. Advances in targeted immunotherapy for hepatobiliary cancers. Int J Mol Sci. 2022;23(22). https://pubmed.ncbi.nlm.nih.gov/36430440/.

  45. Gabriel EM, Kim M, Fisher DT, Mangum C, Attwood K, Ji W, et al. A pilot trial of intravital microscopy in the study of the tumor vasculature of patients with peritoneal carcinomatosis. Sci Rep. 2021;11(1):4946.

    Article  CAS  Google Scholar 

  46. Heilig CE, Horak P, Kreutzfeldt S, Teleanu V, Mock A, Renner M, et al. Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial. ESMO Open. 2021;6(6):100310.

    Article  CAS  Google Scholar 

  47. Varol C, Mildner A, Jung S. Macrophages: development and tissue specialization. Annu Rev Immunol. 2015;33:643–75.

    Article  CAS  Google Scholar 

  48. Jaguin M, Houlbert N, Fardel O, Lecureur V. Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin. Cell Immunol. 2013;281(1):51–61.

    Article  CAS  Google Scholar 

  49. van Dalen FJ, van Stevendaal M, Fennemann FL, Verdoes M, Ilina O. Molecular repolarisation of tumour-associated macrophages. Molecules. 2018;24:1.

    Google Scholar 

  50. Atri C, Guerfali FZ, Laouini D. Role of Human Macrophage Polarization in Inflammation during Infectious Diseases. Int J Mol Sci. 2018;19(6). https://pubmed.ncbi.nlm.nih.gov/29921749/.

  51. Van Overmeire E, Laoui D, Keirsse J, Bonelli S, Lahmar Q, Van Ginderachter JA. STAT of the union: dynamics of distinct tumor-associated macrophage subsets governed by STAT1. Eur J Immunol. 2014;44(8):2238–42.

    Article  Google Scholar 

  52. Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol. 2017;10(1):58.

    Article  Google Scholar 

  53. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124(2):263–6.

    Article  CAS  Google Scholar 

  54. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51.

    Article  CAS  Google Scholar 

  55. Moyes KW, Lieberman NA, Kreuser SA, Chinn H, Winter C, Deutsch G, et al. Genetically engineered macrophages: a potential platform for cancer immunotherapy. Hum Gene Ther. 2017;28(2):200–15.

    Article  CAS  Google Scholar 

  56. Cassier PA, Italiano A, Gomez-Roca C, Le Tourneau C, Toulmonde M, D'Angelo SP, et al. Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour. Eur J Cancer. 2020;141:162–70.

    Article  CAS  Google Scholar 

  57. Rodriguez-Garcia A, Lynn RC, Poussin M, Eiva MA, Shaw LC, O'Connor RS, et al. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy. Nat Commun. 2021;12(1):877.

    Article  CAS  Google Scholar 

  58. First-in-Human Trial with CAR Macrophages Shows the Cell Therapy May Be Safe, Feasible for Solid Tumors [https://www.pennmedicine.org/news/news-releases/2022/january/first-in-human-trial-with-car-macrophages-shows-the-cell-therapy-safe-feasible-for-solid-tumors].

  59. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33.

    Article  CAS  Google Scholar 

  60. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.

    Article  CAS  Google Scholar 

  61. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17.

    Article  Google Scholar 

  62. Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8(355):355ra116.

    Article  Google Scholar 

  63. Kochenderfer JN, Somerville RPT, Lu T, Yang JC, Sherry RM, Feldman SA, et al. Long-duration complete remissions of diffuse large B cell lymphoma after Anti-CD19 chimeric antigen receptor T Cell therapy. Mol Ther. 2017;25(10):2245–53.

    Article  CAS  Google Scholar 

  64. Institute NC: CAR T cells: engineering patients’ immune cells to treat their cancer. 03/10/2022; 2022.

    Google Scholar 

  65. Goff SL, Morgan RA, Yang JC, Sherry RM, Robbins PF, Restifo NP, et al. Pilot trial of adoptive transfer of chimeric antigen receptor-transduced T cells targeting EGFRvIII in patients with glioblastoma. J Immunother. 2019;42(4):126–35.

    Article  CAS  Google Scholar 

  66. O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017;9(399). https://pubmed.ncbi.nlm.nih.gov/28724573/.

  67. Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561–9.

    Article  CAS  Google Scholar 

  68. Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y, et al. CD133-directed CAR T cells for advanced metastasis malignancies: a phase i trial. Oncoimmunology. 2018;7(7):e1440169.

    Article  Google Scholar 

  69. Thistlethwaite FC, Gilham DE, Guest RD, Rothwell DG, Pillai M, Burt DJ, et al. The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol Immunother. 2017;66(11):1425–36.

    Article  CAS  Google Scholar 

  70. Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol. 2017;3(8):1094–101.

    Article  Google Scholar 

  71. Reinhard K, Rengstl B, Oehm P, Michel K, Billmeier A, Hayduk N, et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science. 2020;367(6476):446–53.

    Article  CAS  Google Scholar 

  72. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212–7.

    Article  CAS  Google Scholar 

  73. Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, et al. Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression. Cancer Discov. 2016;6(1):80–95.

    Article  Google Scholar 

  74. Zhang Z, Lu M, Qin Y, Gao W, Tao L, Su W, et al. Neoantigen: a new breakthrough in tumor immunotherapy. Front Immunol. 2021;12:672356.

    Article  CAS  Google Scholar 

  75. Ward JP, Gubin MM, Schreiber RD. The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer. Adv Immunol. 2016;130:25–74.

    Article  CAS  Google Scholar 

  76. Gupta RG, Li F, Roszik J, Lizee G. Exploiting tumor neoantigens to target cancer evolution: current challenges and promising therapeutic approaches. Cancer Discov. 2021;11(5):1024–39.

    Article  CAS  Google Scholar 

  77. Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, et al. Molecular determinants of response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol. 2018;36(7):633–41.

    Article  CAS  Google Scholar 

  78. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.

    Article  CAS  Google Scholar 

  79. Yarchoan M, Johnson BA 3rd, Lutz ER, Laheru DA, Jaffee EM. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer. 2017;17(4):209–22.

    Article  CAS  Google Scholar 

  80. Schumacher TN, Scheper W, Kvistborg P. Cancer Neoantigens. Annu Rev Immunol. 2019;37:173–200.

    Article  CAS  Google Scholar 

  81. Kim S, Kim HS, Kim E, Lee MG, Shin EC, Paik S, et al. Neopepsee: accurate genome-level prediction of neoantigens by harnessing sequence and amino acid immunogenicity information. Ann Oncol. 2018;29(4):1030–6.

    Article  CAS  Google Scholar 

  82. Chu Y, Liu Q, Wei J, Liu B. Personalized cancer neoantigen vaccines come of age. Theranostics. 2018;8(15):4238–46.

    Article  CAS  Google Scholar 

  83. Forghanifard MM, Gholamin M, Moaven O, Farshchian M, Ghahraman M, Aledavood A, et al. Neoantigen in esophageal squamous cell carcinoma for dendritic cell-based cancer vaccine development. Med Oncol. 2014;31(10):191.

    Article  Google Scholar 

  84. Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014;512(7514):324–7.

    Article  CAS  Google Scholar 

  85. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515(7528):577–81.

    Article  CAS  Google Scholar 

  86. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641–5.

    Article  CAS  Google Scholar 

  87. Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science. 2015;350(6266):1387–90.

    Article  CAS  Google Scholar 

  88. Cafri G, Yossef R, Pasetto A, Deniger DC, Lu YC, Parkhurst M, et al. Memory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patients. Nat Commun. 2019;10(1):449.

    Article  CAS  Google Scholar 

  89. Bobisse S, Genolet R, Roberti A, Tanyi JL, Racle J, Stevenson BJ, et al. Sensitive and frequent identification of high avidity neo-epitope specific CD8 (+) T cells in immunotherapy-naive ovarian cancer. Nat Commun. 2018;9(1):1092.

    Article  Google Scholar 

  90. Gros A, Tran E, Parkhurst MR, Ilyas S, Pasetto A, Groh EM, et al. Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes. J Clin Invest. 2019;129(11):4992–5004.

    Article  CAS  Google Scholar 

  91. Esprit A, de Mey W, Bahadur Shahi R, Thielemans K, Franceschini L, Breckpot K. Neo-Antigen mRNA Vaccines. Vaccines (Basel). 2020;8:4.

    Google Scholar 

  92. Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med. 2009;361(19):1838–47.

    Article  CAS  Google Scholar 

  93. Schoenfeld AJ, Hellmann MD. Acquired resistance to immune checkpoint inhibitors. Cancer Cell. 2020;37(4):443–55.

    Article  CAS  Google Scholar 

  94. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, et al. TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest. 2015;125(5):2046–58.

    Article  Google Scholar 

  95. Pawlowska A, Skiba W, Suszczyk D, Kurylo W, Jakubowicz-Gil J, Paduch R, et al. The dual blockade of the TIGIT and PD-1/PD-L1 pathway as a new hope for ovarian cancer patients. Cancers (Basel). 2022;14(23). https://pubmed.ncbi.nlm.nih.gov/36497240/.

  96. Thibaudin M, Limagne E, Hampe L, Ballot E, Truntzer C, Ghiringhelli F. Targeting PD-L1 and TIGIT could restore intratumoral CD8 T cell function in human colorectal cancer. Cancer Immunol Immunother. 2022;71(10):2549–63.

    Article  CAS  Google Scholar 

  97. DePeaux K, Delgoffe GM. Metabolic barriers to cancer immunotherapy. Nat Rev Immunol. 2021;21(12):785–97.

    Article  CAS  Google Scholar 

  98. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69.

    Article  Google Scholar 

  99. Lin Q, Zhao J, Song Y, Liu D. Recent updates on CAR T clinical trials for multiple myeloma. Mol Cancer. 2019;18(1):154.

    Article  Google Scholar 

  100. Dai H, Wu Z, Jia H, Tong C, Guo Y, Ti D, et al. Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. J Hematol Oncol. 2020;13(1):30.

    Article  Google Scholar 

  101. Adusumilli PS, Cherkassky L, Villena-Vargas J, Colovos C, Servais E, Plotkin J, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med. 2014;6(261):261ra151.

    Article  Google Scholar 

  102. Jin L, Tao H, Karachi A, Long Y, Hou AY, Na M, et al. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat Commun. 2019;10(1):4016.

    Article  Google Scholar 

  103. Whilding LM, Halim L, Draper B, Parente-Pereira AC, Zabinski T, Davies DM, et al. CAR T-Cells targeting the integrin alphavbeta6 and co-expressing the chemokine receptor CXCR2 demonstrate enhanced homing and efficacy against several solid malignancies. Cancers (Basel). 2019;11(5). https://pubmed.ncbi.nlm.nih.gov/31091832/.

  104. Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood. 2017;129(8):1039–41.

    Article  CAS  Google Scholar 

  105. Wang Z, Li N, Feng K, Chen M, Zhang Y, Liu Y, et al. Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors. Cell Mol Immunol. 2021;18(9):2188–98.

    Article  CAS  Google Scholar 

  106. Koneru M, Purdon TJ, Spriggs D, Koneru S, Brentjens RJ. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology. 2015;4(3):e994446.

    Article  Google Scholar 

  107. Krenciute G, Prinzing BL, Yi Z, Wu MF, Liu H, Dotti G, et al. Transgenic expression of IL15 improves antiglioma activity of IL13Ralpha2-CAR T cells but results in antigen loss variants. Cancer Immunol Res. 2017;5(7):571–81.

    Article  CAS  Google Scholar 

  108. Mohammed S, Sukumaran S, Bajgain P, Watanabe N, Heslop HE, Rooney CM, et al. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther. 2017;25(1):249–58.

    Article  CAS  Google Scholar 

  109. Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 2015;75(17):3596–607.

    Article  CAS  Google Scholar 

  110. Ying Z, Huang XF, Xiang X, Liu Y, Kang X, Song Y, et al. A safe and potent anti-CD19 CAR T cell therapy. Nat Med. 2019;25(6):947–53.

    Article  CAS  Google Scholar 

  111. Gov CT. CD19-TriCART Phase I; 2018.

    Google Scholar 

  112. TriCAR-T_CD19 Phase II [https://clinicaltrials.gov/ct2/show/NCT03497533].

Download references

Institutional review board statement

Not applicable.

Funding

This work was supported by NIH NCATS grant CCaTS KL2 - TR002379 to Dr. Emmanuel Gabriel.

Author information

Authors and Affiliations

  1. Department of Immunology, Mayo Clinic, Jacksonville, FL, 32224, USA

    Sneha Vivekanandhan & Deborah Bahr

  2. Department of Microbiology, All India Institute of Medical Sciences, Rishikesh, 249203, India

    Ashish Kothari

  3. Department of Surgery, Division of Surgical Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA

    Mohammed Ali Ashary, Mizba Baksh & Emmanuel Gabriel

Authors
  1. Sneha Vivekanandhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deborah Bahr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashish Kothari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammed Ali Ashary
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mizba Baksh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emmanuel Gabriel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, E.G. and S.V.; Writing, review, and editing, S.V., A.K., D.B., M.A. and M.B. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Emmanuel Gabriel.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vivekanandhan, S., Bahr, D., Kothari, A. et al. Immunotherapies in rare cancers. Mol Cancer 22, 23 (2023). https://doi.org/10.1186/s12943-023-01720-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12943-023-01720-2

Keywords

Molecular Cancer

ISSN: 1476-4598