Cancer Vaccine Clinical Trials Research Articles

Abstract 4112: Identification of Th1-specific epitopes from non-mutated KRAS lesions for off-the-shelf cancer vaccines

Abstract Background KRAS is crucial for cell growth, differentiation, and signaling. Mutations in the KRAS gene (i.e., codon 12 or 13) are frequently associated with the development and progression of cancer, particularly lung, colorectal, and pancreatic cancers. Recently, it has been captured that KRAS targeting cancer vaccine research and clinical trials have been conducted in certain tumor types and vaccine approaches are encouraged to move forward. It has been well known that the tumor-eradicating efficacy of cancer vaccines arises from Th1 epitope selection. While tumor growth may persist after immunization with non-selected epitopes (including full-length), immunization with a highly selected Th1-specific epitope vaccine can lead to tumor regression by suppressing the activation of immune inhibitory cells. The Th-Vac® discovery platform uses a combination of in-silico, in-vitro, and in-vivo studies to precisely identify Th1-specific epitopes. It consists of two modules: module 1 (in-silico) and module 2 (in-vitro and efficacy evaluation). The aim is to identify MHC class II epitopes that are specific to antigens for CD4+ T cells, displaying the most favorable binding affinity across diverse alleles. Th1-specific epitope vaccines aim to boost and sustain T cell immunity against tumor antigens, overcoming the lack of a precise T cell response or pre-existing tolerance in the immunosuppressive TME. This study aimed to explore Th1-specific epitopes for KRAS vaccine to be potentially effective in numerous KRAS mutation-driven cancers. Methods Peptide sequence candidates that have highly potential of MHC class II binding affinity were comprehensively predicted via a module 1 (ASEP program). All of peptides selected in ASEP were synthesized as 15 mers. Each peptide was evaluated for immunogenicity using ELISpot and/or FACS analysis in module 2 (2a for in vitro and 2b for in vivo immunologic evaluation) of the Th-Vac® discovery platform. Specifically, in Module 2b, immunogenicity was evaluated using a 38-mer peptide formed by combining five overlapping peptides selected in 2a. These kinds of immunogenicity evaluations were conducted using type 1 and/or type 2 cytokine(s) produced by CD4+ T cells. Results In ASEP prediction, twelve peptides were selected as potential candidates demonstrating a high affinity to MHC class II, which were in different lesions of common mutation of KRAS. In module 2 using ELISpot and FACS analysis, two epitopes (non-mutated sequences) were finally selected as Th1-specific epitopes based on the type 1 T cell response. Conclusion Unlike previous vaccines using mutant lesions, in this study, two non-mutated Th1-specific epitopes are under the in-vivo efficacy studies as mono and combining regimen(s) in certain tumor types. Additionally, the Th-Vac® platform was fully validated in terms of the performance and its application would be expanded beyond a cancer vaccine. Citation Format: Youngki Choi, Jinback Lim, Hyo-Hyun Park, Jinho Kang, Hun Jung. Identification of Th1-specific epitopes from non-mutated KRAS lesions for off-the-shelf cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4112.

Rational design of adjuvants boosts cancer vaccines.

Cancer vaccines are expected to be next breakthrough in cancer immunotherapy. In cancer vaccines, adjuvants play an important role by enhancing and reshaping tumor antigen-specific immune responses. Failures in previous cancer vaccine clinical trials can be attributed to inappropriate selection and design of tumor antigens and adjuvants. Using basic theories of tumor immunology, the development of sequencing technology and nanotechnology enables the creation of cancer vaccines through appropriate selection of tumor antigens and adjuvants and their nanoscale assembly based on the specific characteristics of each tumor. In this chapter, we begin by discussing the various types of cancer vaccines and categories of tumor antigens. Then, we summarize the classification of adjuvants for cancer vaccines, including immunostimulatory molecules and delivery systems, and clarify the various factors that influence the properties of adjuvants, such as chemical composition, structure, and surface modification. Finally, we provide perspectives and insights on rational design of adjuvants in cancer vaccines to enhance their efficacy.

Abstract A003: High-throughput TCR sequencing demonstrates induction of long-lasting HPV16-specific T cell responses in VB10.16 vaccinated advanced cervical cancer patients

Abstract Background: Assessment of vaccine-induced T cell responses is a primary pharmacodynamic readout in cancer vaccine clinical trials. High-throughput sequencing of T cell receptors (TCRs) is emerging as a rapid and scalable method, suitable for late-stage clinical trials, and offers sensitive and accurate quantification of the full T cell repertoire. Here we performed ELISpot and TCR sequencing on serial peripheral blood mononuclear cell (PBMC) samples from a clinical phase 2 trial investigating the therapeutic HPV16 cancer vaccine VB10.16 in combination with atezolizumab in advanced cervical cancer patients (NCT04405349). Methods: T cell responses were assessed by ex vivo IFN-g ELISpot (n=36). Immunosequencing of the TCRB locus was performed in 10 patients with available PBMCs, representing clinical response, stable disease, and progressive disease as best overall response. Immunosequencing of PBMC-derived gDNA was performed on up to five timepoints per patient, ranging from week 10 to 52. Novel and expanded clones from baseline to on-treatment timepoints were determined by a differential abundance framework, using binomial models in pair-wise comparisons, enabling longitudinal tracking of significantly expanded T cell clones. The sequences were matched and annotated to HPV16-specific TCRs present in a proprietary database of confirmed HLA class I HPV16-specific T cell clones; the database was constructed from querying the T cell repertoires of 92 healthy donors with 146 peptides derived from HPV16 E6 and E7 in MIRA assay. Results: An increased T cell response was significantly associated with disease control assessed by RECIST1.1 (n=24 patients with disease control vs n=12 patients with progressive disease, p=0.0113) and patients with a >2-fold increase measured by ex vivo IFN-g ELISpot showed a numerically improved progression-free survival (8 vs 3.7 months median PFS). The longitudinal tracking of TCRs provided a detailed insight into the dynamics of the overall TCR repertoire during treatment. Expansion of both pre-existing and newly expanded T cell clones was observed from week 10 and persisted until the end of treatment. Despite the non-exhaustive database, at least one verified HPV16-specific CD8 T cell clone was expanded in 8 out of 10 patients, supporting that the clonotypic expansion is caused by VB10.16. In 5 out of 7 patients with disease control, the breadth of HPV16-specific TCRs increased after vaccination, demonstrating induction of clinically relevant T cell responses. Conclusions: We demonstrate induction of strong and long-lasting HPV16-specific T cell responses after treatment with VB10.16 and atezolizumab in advanced cervical cancer patients. Induction of HPV16-specific T cell responses was significantly correlated with clinical efficacy. Immunosequencing and HPV16-specific annotation allowed longitudinal tracking of expanded TCRs and demonstrated a potential clinical relevance of increased repertoire diversity of HPV16-specific CD8 T cells in patients. Citation Format: Kaja C G Berg, Paula Bousquet, Milena Blaga, Thomas Bello, Mohammad Arabpour, Mikkel W Pedersen, Karoline Schjetne. High-throughput TCR sequencing demonstrates induction of long-lasting HPV16-specific T cell responses in VB10.16 vaccinated advanced cervical cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A003.

Sending a Message: Use of mRNA Vaccines to Target the Tumor Immune Microenvironment.

While cancer immunotherapies have become central to treatment, challenges associated with the ability of tumors to evade the immune system remain significant obstacles. At the heart of this issue is the tumor immune microenvironment, the complex interplay of the tumor microenvironment and the immune response. Recent advances in mRNA cancer vaccines represent major progress towards overcoming some of the challenges posed by deleterious components of the tumor immune microenvironment. Indeed, major breakthroughs in mRNA vaccine technology, such as the use of replacement nucleotides and lipid nanoparticle delivery, led to the vital success of mRNA vaccine technology in fighting COVID-19. This has in turn generated massive additional interest and investment in the platform. In this review, we detail recent research in the nature of the tumor immune microenvironment and in mRNA cancer vaccines and discuss applications by which mRNA cancer vaccines, often in combination with various adjuvants, represent major areas of potential in overcoming tumor immune microenvironment-imposed obstacles. To this end, we also review current mRNA cancer vaccine clinical trials.

Therapeutic Cancer Vaccines for Nonmelanoma Skin Cancer.

The development of immunotherapies for nonmelanoma skin cancer (NMSC) has lagged far behind that for melanoma in the past few decades, given that the majority of cases are surgically curable. Nevertheless, given the steady growth in the incidence rate of NMSC and attendant increase in patients with unresectable or advanced-stage tumors, the demand for systemic therapy is noticeably increasing. To date, the most widely used immunotherapeutic strategies, including immune checkpoint inhibitors and T-cell therapy, have obtained satisfactory results in some patients but not others. Even with an objective response in a fraction of patients, some accompanying adverse events may lead to intolerance and noncompliance. The expanding understanding of immune surveillance and tumor escape has provided us with novel perspectives in the field of immunotherapy. One emerging approach, the therapeutic cancer vaccine, encompasses the potential to newly "prime" T cells by activating antigen presentation in regional lymph nodes and the tumor microenvironment. Immune cells are therefore preconditioned and awakened to be ready to attack tumors. In NMSCs, multiple clinical trials of cancer vaccines are underway. The vaccine targets include tumor-associated antigens, tumor-specific antigens, oncolytic viruses, and toll-like receptors. Although clinical benefits have been shown in specific case reports and trials, various challenges remain to be resolved to guarantee applicability in the general patient population. Standing on the shoulders of pioneers expedites the pace of advances in therapeutic cancer vaccines, making them the rising star in the field of immunotherapy.

IL-7: A promising adjuvant ensuring effective T cell responses and memory in combination with cancer vaccines?

Cancer vaccines exhibit specificity, effectiveness, and safety as an alternative immunotherapeutic strategy to struggle against malignant diseases, especially with the rapid development of mRNA cancer vaccines in recent years. However, how to maintain long-term immune memory after vaccination, especially T cells memory, to fulfill lasting surveillance against cancers, is still a challenging issue for researchers all over the world. IL-7 is critical for the development, maintenance, and proliferation of T lymphocytes, highlighting its potential role as an adjuvant in the development of cancer vaccines. Here, we summarized the IL-7/IL-7 receptor signaling in the development of T lymphocytes, the biological function of IL-7 in the maintenance and survival of T lymphocytes, the performance of IL-7 in pre-clinical and clinical trials of cancer vaccines, and the rationale to apply IL-7 as an adjuvant in cancer vaccine-based therapeutic strategy.

In silico epitope prediction analyses highlight the potential for distracting antigen immunodominance with allogeneic cancer vaccines.

Allogeneic cancer vaccines are designed to induce antitumor immune responses with the goal of impacting tumor growth. Typical allogeneic cancer vaccines are produced by expansion of established cancer cell lines, transfection with vectors encoding immunostimulatory cytokines, and lethal irradiation. More than 100 clinical trials have investigated the clinical benefit of allogeneic cancer vaccines in various cancer types. Results show limited therapeutic benefit in clinical trials and currently there are no FDA approved allogeneic cancer vaccines. We used recently developed bioinformatics tools including the pVAC-seq suite of software tools to analyze DNA/RNA sequencing data from the TCGA to examine the repertoire of antigens presented by a typical allogeneic cancer vaccine, and to simulate allogeneic cancer vaccine clinical trials. Specifically, for each simulated clinical trial we modeled the repertoire of antigens presented by allogeneic cancer vaccines consisting of three hypothetical cancer cell lines to 30 patients with the same cancer type. Simulations were repeated ten times for each cancer type. Each tumor sample in the vaccine and the vaccine recipient was subjected to HLA typing, differential expression analyses for tumor associated antigens (TAAs), germline variant calling, and neoantigen prediction. These analyses provided a robust, quantitative comparison between potentially beneficial TAAs and neoantigens versus distracting antigens present in the allogeneic cancer vaccines. We observe that distracting antigens greatly outnumber shared TAAs and neoantigens, providing one potential explanation for the lack of observed responses to allogeneic cancer vaccines. This analysis provides additional rationale for the redirection of efforts towards a personalized cancer vaccine approach.

In Silico Model Estimates the Clinical Trial Outcome of Cancer Vaccines.

Over 30 years after the first cancer vaccine clinical trial (CT), scientists still search the missing link between immunogenicity and clinical responses. A predictor able to estimate the outcome of cancer vaccine CTs would greatly benefit vaccine development. Published results of 94 CTs with 64 therapeutic vaccines were collected. We found that preselection of CT subjects based on a single matching HLA allele does not increase immune response rates (IRR) compared with non-preselected CTs (median 60% vs. 57%, p = 0.4490). A representative in silico model population (MP) comprising HLA-genotyped subjects was used to retrospectively calculate in silico IRRs of CTs based on the percentage of MP-subjects having epitope(s) predicted to bind ≥ 1–4 autologous HLA allele(s). We found that in vitro measured IRRs correlated with the frequency of predicted multiple autologous allele-binding epitopes (AUC 0.63–0.79). Subgroup analysis of multi-antigen targeting vaccine CTs revealed correlation between clinical response rates (CRRs) and predicted multi-epitope IRRs when HLA threshold was ≥ 3 (r = 0.7463, p = 0.0004) but not for single HLA allele-binding epitopes (r = 0.2865, p = 0.2491). Our results suggest that CRR depends on the induction of broad T-cell responses and both IRR and CRR can be predicted when epitopes binding to multiple autologous HLAs are considered.

Vaccine Therapies for Cancer: Then and Now

There are strong biologic and preclinical rationales for the development of therapeutic cancer vaccines; however, the clinical translation of this treatment strategy has been challenging. It is now understood that many previous clinical trials of cancer vaccines used target antigens or vaccine designs that inherently lacked sufficient immunogenicity to induce clinical responses. Despite the historical track record, breakthrough advances in cancer immunobiology and vaccine technologies have supported continued interest in therapeutic cancer vaccinations, with the hope that next-generation vaccine strategies will enable patients with cancer to develop long-lasting anti-tumor immunity. There has been substantial progress identifying antigens and vaccine vectors that lead to strong and broad T cell responses, tailoring vaccine designs to achieve optimal antigen presentation, and finding combination partners employing complementary mechanisms of action (e.g., checkpoint inhibitors) to overcome the diverse methods cancer cells use to evade and suppress the immune system. Results from randomized, phase 3 studies testing therapeutic cancer vaccines based on these advances are eagerly awaited. Here, we summarize the successes and failures in the clinical development of cancer vaccines, address how this historical experience and advances in science and technology have shaped efforts to improve vaccines, and offer a clinical perspective on the future role of vaccine therapies for cancer.

TAS0314, a novel multi-epitope long peptide vaccine, showed synergistic antitumor immunity with PD-1/PD-L1 blockade in HLA-A*2402 mice

Cancer peptide vaccines are a promising cancer immunotherapy that can induce cancer-specific cytotoxic T lymphocytes (CTLs) in tumors. However, recent clinical trials of cancer vaccines have revealed that the efficacy of the vaccines is limited. Targeting single antigens and vaccination with short peptides are partly the cause of the poor clinical outcomes. We synthesized a novel multi-epitope long peptide, TAS0314, which induced multiple epitope-specific CTLs in HLA knock-in mice. It also showed superior epitope-specific CTL induction and antitumor activity. We also established a combination treatment model of vaccination with PD-1/PD-L1 blockade in HLA-A*2402 knock-in mice, and it showed a synergistic antitumor effect with TAS0314. Thus, our data indicated that TAS0314 treatment, especially in combination with PD-1/PD-L1 blockade, is a promising therapeutic candidate for cancer immunotherapy.

Immunological effects of adjuvants in subsets of antigen presenting cells of cancer patients undergoing chemotherapy

BackgroundWe have previously shown that HCC patients and healthy subjects are equally responsive to a RNAdjuvant®, a novel TLR-7/8/RIG-I agonist based on noncoding RNA developed by CureVac, by an ex vivo evaluation. However, the immunological effect of adjuvants on immune cells from cancer patients undergoing chemotherapy remains to be demonstrated. Different adjuvants currently used in cancer vaccine clinical trials were evaluated in the present study on immune cells from cancer patients before and after chemotherapy in an ex vivo setting.MethodsPBMCs were obtained from 4 healthy volunteers and 23 patients affected by either colon (OMA) or lung cancer (OT). The effect of CpG, Poly I:C, Imiquimod and RNA-based adjuvant (RNAdjuvant®) was assessed using a multiparametric approach to analyze network dynamics of early immune responses. Evaluation of CD80, CD86 and HLA-DR expression as well as the downstream effect on CD4+ T cell phenotyping was performed by flow cytometry; cytokine and chemokine production was evaluated by Bio-Plex ProTM.ResultsTreatment with RNAdjuvant® induced the strongest response in cancer patients in terms of activation of innate and adoptive immunity. Indeed, CD80, CD86 and HLA-DR expression was found upregulated in circulating dendritic cells, which promoted a CD4+ T cell differentiation towards an effector phenotype. RNAdjuvant® was the only one to induce most of the cytokines/chemokines tested with a pronounced Th1 cytokine pattern. According to the different parameters evaluated in the study, no clear cut difference in immune response to adjuvants was observed between healthy subjects and cancer patients. Moreover, in the latter group, the chemotherapy treatment did not consistently correlate to a significant altered response in the different parameters.ConclusionsThe present study is the first analysis of immunological effects induced by adjuvants in cancer patients who undergo chemotherapy, who are enrolled in the currently ongoing cancer vaccine clinical trials. The results show that the RNAdjuvant® is a potent and Th1 driving adjuvant, compared to those tested in the present study. Most importantly, it is demonstrated that chemotherapy does not significantly impair the immune system, implying that cancer patients are likely to respond to a cancer vaccine even after a chemotherapy treatment.

Human model to predict the outcome of cancer vaccine clinical trials.

e14298 Background: Cancer vaccines activate T-cells with peptides presented by HLA alleles. We hypothesized that peptides binding to multiple HLA alleles of a patient are more likely to induce T-cell responses than epitopes presented by a single HLA. To prove this hypothesis we predicted the outcome of vaccine clinical trials in a Model Population of subjects with complete HLA genotype. Methods: We collected the immune- and objective response rate (IRR, ORR) results from 64 clinical trials conducted in 1,790 patients treated with 42 different vaccines. From these 42 vaccines, we identified personal epitopes (PEPIs) with strong binding affinity to at least 3 HLA alleles of each subject in the Model Population and calculated the proportion of subjects with PEPIs (PEPI Score), multiple PEPIs (MultiPEPI-Score) and PEPIs against multiple vaccine antigens (MultiAg PEPI-Score). Results: Highly significant correlation between the PEPI Score and IRR (p = 0.001) suggests that peptides binding to at least 3 HLA alleles of the subject induce T-cell responses. MultiPEPI-Score correlated with ORR when the tumor of patients expressed the target antigen (p = 0.01). MultiAg PEPI-Score correlated with ORR of clinical trials conducted with vaccines containing multiple antigens (p = 0.01). Conclusions: Our results suggest that (i) a patient’s HLA genotype is the main determinant of vaccine response and (ii) T-cell responses against multiple antigens expressed in the patient’s tumor favors tumor shrinkage. We introduced a novel pre-clinical human model that accurately predicts the outcome of clinical trials, will reduce the risk, cost and time of vaccine development for the prevention and treatment of cancer.

Serum immunoglobulin E response as a marker for unfavorable prognosis following cholesteryl pullulan-MAGE A4 vaccination.

Since 2009, a cancer vaccine clinical trial was conducted with melanoma antigen gene-A4 as an immunogenic agent. The levels of IgG1, IgG2 and IgG3, which are known to be Type 1 T helper cell-associated antibodies, and the levels of IgG4 and IgE, which are known to be Type 2 T helper cell-associated antibodies, were measured and used as biomarkers for predicting therapeutic effect. The results of the present study indicated a strong positive correlation between IgG2 and IgG4, with a correlation coefficient of R=0.808 (P<0.0001). The survival time of patients in which IgE responses were induced was significantly shorter compared with the survival time of patients with no IgE induction. The results of the present study suggest that caution is required when antigen-specific IgE responses are induced during cancer vaccination therapy.

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Cancer vaccine clinical trials.

Cancer vaccine clinical trials.

Antibodies elicited by the first non-viral prophylactic cancer vaccine show tumor-specificity and immunotherapeutic potential.

MUC1 is a shared tumor antigen expressed on >80% of human cancers. We completed the first prophylactic cancer vaccine clinical trial based on a non-viral antigen, MUC1, in healthy individuals at-risk for colon cancer. This trial provided a unique source of potentially effective and safe immunotherapeutic drugs, fully-human antibodies affinity-matured in a healthy host to a tumor antigen. We purified, cloned, and characterized 13 IgGs specific for several tumor-associated MUC1 epitopes with a wide range of binding affinities. These antibodies bind hypoglycosylated MUC1 on human cancer cell lines and tumor tissues but show no reactivity against fully-glycosylated MUC1 on normal cells and tissues. We found that several antibodies activate complement-mediated cytotoxicity and that T cells carrying chimeric antigen receptors with the antibody variable regions kill MUC1+ target cells, express activation markers, and produce interferon gamma. Fully-human and tumor-specific, these antibodies are candidates for further testing and development as immunotherapeutic drugs.

713. Optimization and Scale-Up of a Manufacturing Process for Clinical-Grade Adenovirus-Based Vectors

We have developed a manufacturing protocol for clinical-grade Adenovirus-based vectors utilizing suspension 293 cells grown with chemically defined media in disposable spinner flasks. We have manufactured four batches of clinical-grade Adenovirus vectors utilizing this protocol, and some vectors have been administered in TB or cancer vaccine clinical trials in Canada. The maximum volume for a batch was from a 30-liter infected cell culture consisting of three lots with 10 liters. Each 10-liter lot was purified by cesium chloride density gradient ultracentrifugation and desalted by a Biogel column. The purified vectors were then pooled, filtered and filled into cryovials.In an effort to increase manufacturing capacity, we have investigated the use of a Pall XRS-20 Bioreactor with a maximum cell culture capacity of 20 liters. We assessed cell growth kinetics/infection kinetics and found that at the minimum, we can achieve triple the maximum cell density compared with the use of spinner flasks. We have observed virus yields similar to what can be achieved with spinner flasks, and are currently optimizing the infection protocol to assess if virus yields can still be improved.In order to address the scale-up concerns associated with the cesium chloride density gradient ultracentrifugation method, we are also developing a chromatography-based virus purification protocol. We are using a high-throughput test protocol to identify the critical process parameters (e.g. specific buffer species, pH, ionic strength) in resin binding experiments that achieve the required removal of impurities but also maintain immunogenic activity. A design-of-experiment strategy is being used to minimize the overall number of experiments.

CpG-mediated augmentation of CD8+ T-cell responses in mice is attenuated by a water-in-oil emulsion (Montanide ISA-51) but enhanced by an oil-in-water emulsion (IDRI SE).

Adjuvants are a key component in enhancing immunogenicity of vaccines and play a vital role in facilitating the induction of the correct type of immunity required for each vaccine to be optimally efficacious. Several different adjuvants are found in licensed vaccines, and many others are in pre-clinical or clinical testing. Agonists for TLRs are potent activators of the innate immune system and some, such as CpG (TLR9 agonist), are particularly good for promoting cellular immunity because of the induction of Th1 cytokines. Emulsions that have both delivery and adjuvant properties are classified as water-in-oil (W/O) or oil-in-water (O/W) formulations. The W/O emulsion Montanide ISA-51, often combined with CpG, has been widely tested in cancer vaccine clinical trials. Squalene-based O/W emulsions are in licensed influenza vaccines, and T-cell responses have been assessed pre-clinically. No clinical study has compared the two types of emulsions, and the continued use of W/O with CpG in cancer vaccines may be because the lack of single adjuvant controls has masked the interference issue. These findings may have important implications for the development of vaccines where T-cell immunity is considered essential, such as those for cancer and chronic infections. Using particulate (hepatitis B surface antigen) and soluble protein (ovalbumin) antigen, we show in mice that a W/O emulsion (ISA-51) abrogates CpG-mediated augmentation of CD8(+) T-cell responses, whereas a squalene-based O/W emulsion significantly enhanced them.

Abstract IA09: Reprogramming T cells for adoptive immunotherapy of ovarian cancer.

Abstract The goal of our studies is to generate robust and long-lasting tumor-specific T cell responses for durable tumor regression in patients with epithelial ovarian cancer (EOC). While the majority of women with advanced stage EOC initially respond to surgery and first-line chemotherapy, more than 70% of patients eventually die of recurrent disease within 5 years of diagnosis. In an effort to generate tumor-associated antigen (TAA) specific T cells for the treatment of EOC patients, our team has identified NY-ESO-1 as the prototypic TAA for immunotherapy in ovarian cancer. In clinical trials of cancer vaccines conducted by our group, although active immunization targeting NY-ESO-1 can generate TAA specific effector T cells, the long term control of ovarian cancer is infrequent. This is primarily because of the relatively low magnitude and short in vivo lifespan of the vaccine-elicited T cells limited long-term tumor control in the patients. Consequently, we have focused on genetically re-engineering T cells to express a NY-ESO-1 specific CD8+ T cell receptor (CD8TCR), followed by adoptive transfer of these cells into EOC patients. Although this approach led to large numbers of circulating tumor antigen specific T cells and tumor regression, the strategy is hampered by the relatively short lifespan of the effector CD8+ T cells. These results indicate that lack of sustained expansion of long lasting, durable tumor specific T cells is a major obstacle for successful adoptive T cell therapy. In preliminary studies, we have focused on CD4+ T cells as the major driver of anti-tumor immunity. In order to augment the in vivo persistence of the engineered CD8TCR cells, we have cloned a distinct subset of human CD4+ Th1 cells that directly recognize NY-ESO-1 naturally presented by MHC class II on cancer cells. In addition, these tumor-recognizing CD4+ T cells (TR-CD4TCR) potently provide help to CD8TCR cells in an antigen-presenting cell (APC) independent fashion and amplify the anti-tumor effects of CD8+ T cells. In contrast, their conventional TAA-specific CD4+Th1 counterparts (non-tumor recognizing, NTR-CD4), require APCs for their activation. Direct cognate interaction between TR-CD4 and cancer cells triggers the release of an array of effector molecules which inhibit tumor growth and amplify the anti-tumor effects of CD8+ T cells. We have also demonstrated that human hematopoietic stem/progenitor cells (hHSC) can be genetically re-programmed for continuous generation of long lived tumor-specific T cells in an NSG mouse model. We propose a novel clinical application of hHSCs for the continuous (possibly lifelong) source of anti-cancer immune cells that will provide sustained attack against cancer cells. Citation Format: Kunle Odunsi. Reprogramming T cells for adoptive immunotherapy of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA09.

Abstract A169: NY-ESO-1 protein cancer vaccine with TLR 3 and 4 agonists

Abstract NY-ESO-1 is expressed in wide range of human malignancies expect testis in normal tissues and induces spontaneous antibody in patients with cancers expressing NY-ESO-1. Because of its unique expression and high immunogenicity, NY-ESO-1 is promising as a target of cancer vaccine. We have conducted serial clinical trials with the NY-ESO-1 protein since 2004 and antigen-specific immune responses were observed in most of patients immunized. Some patients showed feasible clinical responses however they were limited and novel immune modulators which could make NY-ESO-1 protein vaccination effective are needed. Recently, stimulation through the Toll-like receptors (TLRs) enhance the induction of antigen-specific immune responses upon cancer vaccine has become apparent. In this study, we conducted a phase I cancer vaccine clinical trial using NY-ESO-1 protein combined with Poly ICLC and Picibanil OK-432 as TLR 3 and 4 agonist, respectively. This trial was designed to evaluate the safety, induction of immune response and clinical response. Patients with advanced cancers expressing NY-ESO-1 were eligible. 200μg NY-ESO-1 protein mixed with Montanide in combination of Poly ICLC and/or Picibanil OK-432 was administered subcutaneously once every 2 weeks in six times. Seven patients with esophageal cancer, three with gastric cancer, two with lung cancer, two with ovarian cancer and one with malignant melanoma were enrolled in four groups, i) NY-ESO-1 protein alone (n=3), ii) NY-ESO-1 protein with OK-432 (n=3), iii) NY-ESO-1 protein with Poly ICLC (n=3), iv) NY-ESO-1 protein with OK-432 and Poly ICLC (n=6). All patients developed an injection-site reaction and fever (grade1 or 2) but no severe adverse events related to the drug were observed. An increase in the NY-ESO-1 antibody response was observed in all patients after vaccination. Earlier induction and higher frequency of NY-ESO-1 responsible T cells were observed in patients immunized with Poly ICLC than those without Poly ICLC. NY-ESO-1 protein vaccine with Poly ICLC and OK432 was safe and antigen-specific immune responses were induced in all patients. TLR agonists would be useful and effective immune modulators for cancer vaccines. Citation Format: Tomohira Takeoka, Hirotsugu Nagase, Yasuhiro Miyazaki, Tsuyoshi Takahashi, Yukinori Kurokawa, Tomoki Makino, Makoto Yamasaki, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Hisashi Wada. NY-ESO-1 protein cancer vaccine with TLR 3 and 4 agonists. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A169.