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Efficient Tumor Clearance and Diversified Immunity Through Neoepitope Vaccines and Combinatorial Immunotherapy

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Efficient Tumor Clearance and Diversified Immunity Through Neoepitope Vaccines and Combinatorial Immunotherapy Published OnlineFirst July 10, 2019; DOI: 10.1158/2326-6066.CIR-18-0620 Research Article Cancer Immunology Research Efficient Tumor Clearance and Diversified Immunity through Neoepitope Vaccines and Combinatorial Immunotherapy Karin L. Lee1, Stephen C. Benz2, Kristin C. Hicks1, Andrew Nguyen2,Sofia R. Gameiro1, Claudia Palena1, John Z. Sanborn2, Zhen Su3, Peter Ordentlich4, Lars Rohlin5, John H. Lee6, Shahrooz Rabizadeh2,5, Patrick Soon-Shiong2,5, Kayvan Niazi5, Jeffrey Schlom1, and Duane H. Hamilton1 Abstract Progressive tumor growth is associated with deficits in the tumor immunosuppression, and a tumor-targeted IL12 immunity generated against tumor antigens. Vaccines target- molecule to facilitate T-cell function within the tumor ing tumor neoepitopes have the potential to address qualita- microenvironment. Analysis of tumor-infiltrating leuko- tive defects; however, additional mechanisms of immune cytes demonstrated this multifaceted treatment regimen was þ failure may underlie tumor progression. In such cases, patients required to promote the influx of CD8 Tcellsandenhance would benefit from additional immune-oncology agents tar- the expression of transcripts relating to T-cell activation/ geting potential mechanisms of immune failure. This effector function. Tumor-targeted IL12 resulted in a marked study explores the identification of neoepitopes in the MC38 increase in clonality of T-cell repertoire infiltrating the colon carcinoma model by comparison of tumor to normal tumor, which when sculpted with the addition of either a DNA and tumor RNA sequencing technology, as well as peptide or adenoviral neoepitope vaccine promoted effi- neoepitope delivery by both peptide- and adenovirus-based cient tumor clearance. In addition, the neoepitope vaccine vaccination strategies. To improve antitumor efficacies, we induced the spread of immunity to neoepitopes expressed combined the vaccine with a group of rationally selected by the tumor but not contained within the vaccine. These immune-oncology agents. We utilized an IL15 superagonist results demonstrate the importance of combining neoepi- to enhance the development of antigen-specific immunity tope-targeting vaccines with a multifaceted treatment regi- initiated by the neoepitope vaccine, PD-L1 blockade to reduce men to generate effective antitumor immunity. Introduction ronment (3) impact the ability of reactive T cells expanded by neoepitope vaccines to cause the regression of established tumors. The development of vaccines targeting nonsynonymous muta- The selection of appropriate neoepitopes to target continues to tions uniquely expressed by a tumor has become a viable ther- be a challenge. In this study, we observed that using a combina- apeutic strategy, and the potential of expanding a pool of high- tion of in silico analysis, along with both in vitro and in vivo studies avidity T cells capable of mediating tumor clearance holds the aimed at enriching for immunogenic neoepitopes, was not suf- promise of revolutionizing the treatment of cancer. However, the ficient to identify neoepitopes capable of mediating tumor regres- presence of regulatory T cells (1), dysregulation of immune sion when utilized as a single agent. To improve the clinical checkpoints (2), and an immune-suppressive tumor microenvi- efficacy of this neoepitope-targeted vaccine, we combined it with three additional immune-oncology agents. Together, these agents act to (i) initiate the immune response, (ii) potentiate systemic antitumor immunity, (iii) reduce tumor-associated immune-sup- 1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. 2NantOmics, LLC, Culver City, California. 3EMD pression, and (iv) facilitate the expansion and function of T cells Serono Research and Development Institute, Billerica, Massachusetts. 4Syndax, within the tumor microenvironment. Waltham, Massachusetts. 5NantBio, Inc, & ImmunityBio, Culver City, California. Previously, Yadav and colleagues (4) identified three neoepi- 6Chan Soon-Shiong Institute for Medicine, El Segundo, California. topes in the MC38 colon cancer model and demonstrated that Note: Supplementary data for this article are available at Cancer Immunology vaccination was able to induce tumor regression; tumors were Research Online (http://cancerimmunolres.aacrjournals.org/). induced using a low dose of MC38 tumor cells that results in a J. Schlom and D.H. Hamilton contributed equally to this article. slow-growing tumor, which is exceptionally responsive to immune interventions such as PD-L1 blockade (5). In those Corresponding Author: Jeffrey Schlom, NCI, 10 Center Drive, Building 10, studies, adjuvant alone induced tumor regression in 40% of Rm. 8B09, Bethesda, MD 20892. Phone: 240-858-3463; Fax: 240-541-4558; E-mail: [email protected] animals. In this study, we implanted animals with a higher dose of MC38 tumor cells that results in a faster growing tumor, Cancer Immunol Res 2019;7:1359–70 which is more resistant to immune interventions (6). To ensure doi: 10.1158/2326-6066.CIR-18-0620 our therapeutic regimen has a clear translational path, we Ó2019 American Association for Cancer Research. employed agents that have undergone or are undergoing clinical www.aacrjournals.org 1359 Downloaded from cancerimmunolres.aacrjournals.org on September 23, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 10, 2019; DOI: 10.1158/2326-6066.CIR-18-0620 Lee et al. evaluation (7–9). In this study, the antitumor immune response Identification of tumor variants and neoepitopes was initiated using either a peptide- or adenoviral-based vaccine Single-nucleotide variants (SNV) and insertions/deletions targeting immunogenic neoepitopes identified in the MC38 colon (indel) were identified as previously described (26). Neoepitopes carcinoma cell line. This immunity was potentiated systemically were identified by creating all possible permutations of 9-mer with the addition of the IL15 superagonist N-803 (previously amino acid sequences derived from an identified nonsilent SNV known as ALT-803), which has been shown to be 4- to 5-fold more or indel. Neoepitopes were ranked by RNA expression as well as potent than IL15 (10, 11), and promotes the expansion, survival, allele frequency of the observed coding variant to offset issues and function of high-avidity memory T cells, without expanding arising from tumor heterogeneity. NetMHC 3.4 (http://www.cbs. the regulatory T-cell compartment (12–17). PD-L1 blockade was dtu.dk/services/NetMHC-3.4/; refs. 27, 28) was used to predict added to our treatment regimen to inhibit tumor immune eva- neoepitope binding to a specific MHC H-2 allele. Neoepitopes sion, help prevent T-cell exhaustion and promote T-cell function with predicted binding affinities <500 nmol/L were retained for within the tumor microenvironment. The immunocytokine NHS- further analysis. Raw sequencing data from high-throughput IL12 comprises IL12 fused with a necrosis-targeting antibody, sequencing was deposited in BioProject Accession PRJNA551473 which targets IL12 to the tumor to promote T-cell expansion and (https://www.ncbi.nlm.nih.gov/bioproject/551473). function within the tumor microenvironment (18). We observed that each agent acted in concert to promote the generation and Peptide synthesis maintenance of the tumor-specific immune response capable of Peptides were synthesized by Bio-Synthesis or GenScript to mediating efficient tumor regression. >85% purity. The expression of tumor neoepitopes can vary greatly among cells comprising the tumor mass (19–25). Thus, the generation of Cell isolation and preparation a diverse immune repertoire capable of recognizing numerous Spleens were harvested, dissociated through 70-mm filters, and neoepitopes is well suited to control the growth of numerous subjected to ACK lysis to obtain splenocytes for analysis. Tumors tumor variants. In this study, we observed that vaccines targeting were harvested, cut into small pieces, and incubated for 1 hour neoepitopes induced the in situ spread of immunity to other in a digestion cocktail composed of RPMI supplemented with 5% neoepitopes expressed by the tumor, but not incorporated into (v/v) FBS, 2 mg/mL Collagenase Type I (Worthington Biochem- the vaccine. Our data suggest that this epitope spreading is an ical Corporation), and 40 U/mL DNase I (Calbiochem). Follow- essential aspect of an effective antitumor immune response. This ing digestion, tumors were ground through 70-mm filters and report demonstrates the importance of a multifaceted immuno- tumor-infiltrating leukocytes (TIL) were enriched using a 40%/ therapy treatment regimen targeting different potential facets of 70% Percoll (Sigma) gradient. Peripheral blood mononuclear immune failure in the development and maintenance of a diverse, cells (PBMC) were isolated from whole, anticoagulated mouse effective antitumor immune response capable of mediating blood by layering over lymphocyte separation medium (MP tumor regression. Biomedicals) and collecting lymphocyte layer. Our studies demonstrate that (i) the effectiveness of neoepi- tope-targeted vaccines can be improved via the addition of ratio- Flow cytometric assays nally selected immune-oncology agents, (ii) adenoviral-based All antibodies used for flow cytometric analysis are fully vaccines encoding neoepitopes, when used in combination with described in Supplementary Table S1. Peptide-binding assays additional immune-mediators, can mediate tumor regression, were performed using RMA-S cells incubated with individual
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