ATLAS™-identified “inhibitory” neoantigens
promote tumor growth in mouse model
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.
Forward-Looking StatementsThis 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.
Contact: Jennifer LaVin
617-715-6687jennifer.lavin@genocea.com
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