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Genocea Unveils Possible Mechanism for Tumor Resistance to Immunotherapy at Society for Immunotherapy of Cancer’s (SITC) 33rd Annual Meeting
ATLAS™-identified “inhibitory” neoantigens promote tumor growth in mouse model
ATLAS platform continues to differentiate versus in silico methods for true neoantigen identification
CAMBRIDGE, Mass., Nov. 06, 2018 (GLOBE NEWSWIRE) -- Genocea Biosciences, Inc. (NASDAQ: GNCA), a biopharmaceutical company developing personalized cancer immunotherapies, today highlighted data from poster presentations at the 33rd Annual Meeting of The Society for Immunotherapy of Cancer (SITC) taking place November 7 to 11, 2018 at the Walter E. Washington Convention Center in Washington, D.C.
Jessica B. Flechtner, Ph.D., Genocea’s chief scientific officer, provided context: “We are pleased to share new data suggesting the potential deleterious effect of what we term “inhibitory” neoantigens because of their association with inhibition of T cell responses to tumors. Our new data in a mouse model present early evidence that these neoantigen-specific inhibitory responses, which we frequently identify in human subjects, may be tumor-promoting. Even as we continue to explore the mechanism of such responses, we are confident that their identification will play an important role in creating best-in-class cancer immunotherapies and in a better understanding of cancer treatment resistance. We believe our posters offer a comprehensive snapshot of how our ATLAS platform differentiates Genocea from our peers, the majority of whom use in silico methods to predict neoantigens and who consequently have no means of identifying inhibitory neoantigens.”
Kwok-Kin Wong, M.D., Ph.D, Chief of Hematology and Medical Oncology, New York University Langone Health Center, also commented on the data: “Personalizing a vaccine by selecting neoantigens that are recognized by the patient’s own immune system certainly avoids any limitations from in silico selection. However, the novel discovery in ATLAS that many mutations may have a patient-specific immune suppressive effect raises provocative questions as to the importance of identifying and excluding these sequences from immunotherapies.”
The following posters will be located in Poster Hall E and presented on Saturday, November 10 from 12:20 – 1:50 p.m. and 7:00 – 8:30 p.m. ET.
Summary of Poster #P166 – Ex vivo ATLAS-identified inhibitory neoantigens promote mouse melanoma tumor progression
• ATLAS performed on splenocytes from untreated tumor-bearing mice identified that, of the >1,600 mutations identified in the B16F10 melanoma, 4% elicited stimulatory and 3% elicited inhibitory T cell responses, defined as a statistical increase or decrease in beneficial cytokine secretion, respectively, relative to baseline controls.
• MHC-binding prediction algorithms failed to identify the majority of ATLAS-identified neoantigens (<10% PPV); in addition, approximately half of the neoantigens accurately predicted by algorithms were shown by ATLAS to be inhibitory, which could not have been predicted.
• Immunization with inhibitory neoantigens led to hyperprogression in some mice. Hyperprogression has been observed in some human subjects treated with checkpoint blockade drugs. These data suggest inhibitory responses to neoantigens may play an important role in the observation.
• Stimulatory peptide antigens combined with adjuvant were immunogenic and promoted anti-tumor response. These may ultimately be enhanced when combined with checkpoint blockade therapy.
Summary of Poster #P154 – Empiric profiling of neoantigen-specific T cell responses in NSCLC patients with ATLAS™ reveals unexpected neoantigen and inhibitory antigen profiles
• More than 1,000 putative neoantigens were screened using autologous antigen-presenting cells and T cells from 9 individuals with small cell or non-small cell lung cancer.
• ATLAS empirically identified which somatic mutations from each patient's tumor were neoantigens, independently of HLA type and without predictions, including which were stimulatory and which were inhibitory.
- Overall, approximately equal proportions of inhibitory and stimulatory antigens were identified.
- Most of the antigens were not predicted by algorithms or enriched by other classifiers such as expression level, mutation type, or predicted mutant to wild-type peptide binding affinity ratios.
- There is little overlap between CD4+ and CD8+ T cell antigens; less than 2% of neoantigens were shared between T cell subsets in the study.
• Patients who failed to respond to checkpoint blockade therapy often had a greater proportion of inhibitory to stimulatory neoantigens.
Summary of Poster #P174 – A phase 1/2a study to evaluate the safety, tolerability, immunogenicity, and anti-tumor activity of GEN-009 adjuvanted neoantigen vaccine in adult patients with selected solid tumors
• Study design of GEN-009-101 – trial initiated in August 2018 with initial immunogenicity data expected in the first half of 2019.
• First trial to use ATLAS-identified, stimulatory neoantigens as part of a personalized vaccine:
- Part A: monotherapy in patients with no evidence of disease, high risk of relapse (n=6-9)
- NSCLC, urothelial, melanoma, HNSCC
- Readouts: safety and immunogenicity
- Part B: combination therapy with nivolumab. Patients with stable disease or PR (n=15 per cohort)
- NSCLC, urothelial, melanoma, HNSCC, RCC
- Readouts: safety, immunogenicity, efficacy
- Part C: monotherapy in patients with relapsed/refractory disease (n≤40 patients)
- Same indications as Part B
- Readouts: safety, immunogenicity, efficacy
• Immunogenicity readouts will include: ex vivo dual fluorospot IFN-gamma/Granzyme B to detect CD4+ and CD8+ T cell responses to each SLP, cultured fluorospot, CD4+ and CD8+ polyfunctional responses by intracellular cytokine staining, immunophenotyping PBMC, and tumor biopsy assessments using RNAseq and immunofluorescence
• Efficacy readouts will include:
- Part A: disease-free survival
- Part B: response improvement rate, duration of response, progression-free survival
- Part C: objective response rate, duration of response, progression-free survival
About Genocea Biosciences, Inc.
Genocea's mission is to help conquer cancer by designing and delivering targeted vaccines and immunotherapies. While traditional immunotherapy discovery methods have largely used predictive methods to propose T cell targets, or antigens, Genocea has developed ATLAS™, its proprietary technology platform, to identify clinically relevant antigens of T cells based on actual human immune responses. Genocea is using ATLAS to develop cancer vaccines and immunotherapies. Genocea is currently studying the safety, immunogenicity, and efficacy of its lead neoantigen cancer vaccine, GEN-009, in a Phase 1/2a clinical trial. For more information, please visit www.genocea.com.
This press release includes forward-looking statements, including statements relating to the expected clinical development of GEN-009 and the potential role of inhibitory neoantigens in the field of immuno-oncology, within the meaning of the Private Securities Litigation Reform Act. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Genocea cautions that these forward-looking statements are subject to numerous assumptions, risks and uncertainties that change over time. Applicable risks and uncertainties include those identified under the heading "Risk Factors" included in Genocea's Annual Report on Form 10-K for the year ended December 31, 2017 and any subsequent SEC filings. These forward-looking statements speak only as of the date of this press release and Genocea assumes no duty to update forward-looking statements, except as may be required by law.