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Neoepitopes As Difference Makers for General Cancer Vaccines?

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Neoepitopes As Difference Makers for General Cancer Vaccines? Author Manuscript Published OnlineFirst on July 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2127 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Neoepitopes as difference makers for general cancer vaccines? Jessica N. Filderman, B.S.1 and Walter J. Storkus, Ph.D.1-5 From the Departments of 1Immunology, 2Dermatology, 3Pathology and 4Bioengineering, University of Pittsburgh School of Medicine and the 5Hillman Cancer Center, Pittsburgh, PA 15213. Correspondence to: Walter J. Storkus, Ph.D. W1151 Biomedical Science Tower Department of Dermatology University of Pittsburgh School of Medicine 200 Lothrop Street Pittsburgh, PA 15213 Tel: 412-648-9981 FAX: 412-383-5857 Email: [email protected] Running Title: Cancer neoepitopes as difference makers (39 characters) Conflicts of Interest: The author has no conflict of interest. Funding: This work was support by NIH T32 CA082084 (JNF) and NIH R01 CA204419 (WJS). Title characters: 61 Text Words: 1,024 Summary Words: 50 References: 5 Figures: 1 1 Downloaded from clincancerres.aacrjournals.org on October 6, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2127 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. SUMMARY: The cancer mutanome has been associated with disease prognosis as well as response to interventional immunotherapy and provides a substrate for development of personalized vaccines targeting tumor neoepitopes. Recent findings suggest that neoantigen-based vaccines may represent general interventional approaches for patients with solid cancers, regardless of their inherent mutational burden. MAIN TEXT: In this issue of Clinical Cancer Research, Fang and colleagues1 report results from their single- arm, open-labeled, investigator-initiated clinical trial (NCT03662815) involving 22 advanced- stage patients treated with personalized peptide-based mutated neoantigen vaccines (designated iNeo-Vac-P01) conducted over the period of 2/2018 - 5/2019. Recruited patients had failed prior standard of care regimens and presented with one of 11 different forms of solid cancer. A general paradigm for neoantigen-based vaccine development and application in cancer patients is outlined in Fig. 1. In the report by Fang et al.1, patient-specific mutated neoantigens and derivative MHC-presented peptide epitopes encompassing mutant sequences were determined by bioinformatics analyses (iNeo-Suite) based on comparing whole-exome sequencing (WES) data from patient-matched tumor (mutated) vs. peripheral blood specimens (genomic control). Pooled peptide vaccines (5-20 peptides with each peptide 15-35 amino acids in length) were delivered s.c. in the upper arms and para-umbilical area along with adjuvant rhGM-CSF in an accelerated priming schedule (days 1, 4, 8, 15, 22), with follow-up booster vaccines. In keeping with past trials of cancer neoantigen vaccines2, the current vaccines were well-tolerated, with only 2 patients developing grade 3 or 4 acute allergic reactions but only after repeated (6) booster immunizations, necessitating treatment discontinuation. The study disease control rate (DCR) was 71.4%, with a median progression-free survival (PFS) of 4.6 months, and the median overall survival (OS) not yet reached at the time of this report (12-month OS = 55.1%). Consistent with the published clinical experience for personalized neoantigen-based vaccines, and the expectation that (somatically) mutated tumor neoantigens are not subjected to central immune tolerance mechanisms in the host2, the majority of neoantigen-derived peptides (~ 80%) evaluated in the current study were capable of eliciting specific responses from patient peripheral blood T cells after vaccination based on IFN- ELISPOT assays. Furthermore, the vast majority (~90%) of evaluable patients exhibited on-treatment T cell responses to their personalized iNeo-Vac-P01 vaccine based on IFN- ELISPOT assays and the presence of high- abundance T cell clonotypes in peripheral blood, deduced by TCRBseq analyses. Multi- 2 Downloaded from clincancerres.aacrjournals.org on October 6, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2127 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. parameter immunofluorescence analyses of on-treatment tumor biopsy specimens from 3 patients revealed increased numbers of GZMB+ CD8+ and CD4+ tumor-infiltrating lymphocytes (TIL) 5.5-9 months after initial vaccine priming. The current trial is remarkable in demonstrating immunologic, and to a lesser degree clinical, response to neoantigen-based vaccination in a comparatively large number of patients harboring extremely diverse forms of cancer. Previous trials of tumor neoantigens accrued smaller numbers of patients and were restricted to single types of cancer2. Personalized iNeo- Vac-P01 vaccines were efficiently generated within a short 1.5 - 3 month period regardless of patient cancer histotype, stressing the feasibility of applying this approach in the broader cancer setting, even in cases at higher risk for rapid progression. Importantly, these vaccines were shown to be immunogenic in patients (based on iRECIST criteria) harboring consensus high (i.e. melanoma) as well as low (i.e. pancreatic carcinoma) tumor mutation burden (TMB), jibing with published results for smaller clinical trials of neoantigen vaccines in melanoma (high TMB) or glioma (low TMB) patients2. Despite evidence for near universal patient immune responsiveness to vaccination with iNeo-Vac-P01 vaccines, no patients achieved complete or partial response (CR or PR) (i.e. best tumor shrinkage = ~17%), although some patients exhibited on-treatment pseudoprogression of (advanced hepatic biliary tract cancer) lesions or regression of liver metastasis (pancreatic carcinoma). These latter data are intriguing given the dismal prognosis for patients with advanced-stage pancreatic carcinoma or biliary tract cancer, suggesting that further optimization of the iNeo-Vac-P01 immunotherapeutic platform might fill the current void for effective treatment options in these patient cohorts. A conundrum remaining to be addressed at the bench and in prospective clinical trials of tumor mutant neoantigen-based vaccines reflects the “elephant in the room”; i.e. the striking disconnect between treatment immunogenicity and evidence for therapeutic (RECIST1.1) benefit in patients with multi-focal disease. Simple considerations include insufficient numbers or quality of T cells elicited with neoepitope + GM-CSF-based vaccines in the face of dominant immunosuppression in the tumor microenvironment (TME) in the current report that might be improved in formulations using alternate adjuvants (i.e. TLR agonists, dendritic cells), or inefficient recruitment of circulating vaccine-induced T cells into the TME that could be improved by combining vaccines with a range of co-immunotherapeutic agents including checkpoint blockade, costimulatory agonists, TLR/STING agonist, oncolytic viruses, adoptive cell therapy, radiotherapy, among others (Fig. 1). A more likely consideration reflects the nightmarish 3 Downloaded from clincancerres.aacrjournals.org on October 6, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2127 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. logistics in correctly identifying and clinically-applying in silico-selected neoantigenic epitopes that are both naturally-processed and presented in sufficient stochastic quantities in MHC complexes on the tumor cell surface to allow for recognition by even high-avidity cognate T cells that have escaped central tolerance2. For instance, even tumor infiltrating lymphocytes (TIL) and mass spectroscopy are only able to effectively identify 1-5% of in silico predicted neoepitopes as being naturally-processed and MHC-presented on the tumor cell surface3. This selection burden is made greater given known tumor heterogeneity with regards to antigenicity and immunogenicity (i.e. variance in antigen processing and MHC presentation machinery) within a given patient lesion as well as between distinct lesions in patients with multi-focal, disseminated disease, where epitopes in driver or truncal mutated neoantigens4 might represent particularly salient targets. In the end, while refinement in predictive algorithms may improve identification of tumor neoepitopes that serve as rejection antigens, we will likely have to depend on a strength in numbers approach. In such a scenario, even one correctly predicted “natural” neoepitope in a multi-peptide vaccine might prove sufficient to evoke therapeutic benefit, or to allow that vaccine to elicit the evolution of spreading in the T cell repertoire to reinforce reactivity against naturally- presented cancer mutated neoepitopes not present in the priming vaccine (Fig. 1). Clearly, the ability of checkpoint blockade interventions5 to uncover T cell responses against mutant tumor neoantigens that are prognostic of treatment outcome bodes well for the development of combined treatment modalities integrating personalized vaccines such as iNeo-Vac-P01 (Fig. 1). Hence, while there is clearly much work left to do, the report by Fang et al.1 engenders significant
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