Abstract 1674P
Background
Checkpoint inhibitors are ineffective in cold tumors with low T cell infiltration. Results from our phase IIa study suggest that subjects responding to NT-I7 plus pembrolizumab (pembro) had enhanced lymphocyte infiltration. To confirm, we analyzed immune-associated changes in the tumor microenvironment (TME) after NT-I7 plus pembro.
Methods
NT-I7 (efineptakin alfa) 1,200 μg/kg every 6 weeks (Q6W) and pembro 200 mg Q3W were administered in MSS-Colorectal, Pancreatic and Ovarian Cancer. Peripheral blood samples and tumor biopsies were obtained pre- and post-treatment. The TME was analyzed by immunofluorescence (mIF), flow cytometry, TCRseq and whole transcriptome sequencing. 39 subjects had suitable biopsies and 56.4% (22/39) had at least two consecutive tumor assessments at the time of the analysis. Nonparametric tests and linear regression were used for statistical analysis.
Results
91.7% (11/12; 79-373 cells/mm2, p=0.0263) and 73.3% (11/15; 0.2-1.1% of total cells, p=0.0215) of samples analyzed by mIF and flow cytometry, respectively, had increased CD8 T cell infiltration. 51.7% of samples (15/29) showed at least a 5-fold increase in CD8 T cells. Peripheral stem-cell memory CD8 T cells (TSCM), a subset increased by NT-I7, was directly associated with the CD8 T cell infiltration. Infiltrating CD8 T cells expressed PD-1 and gene set enrichment analysis showed an increase in immune- and lymphocyte activation-related genes post-treatment, suggesting that infiltrating CD8 T cells are tumor-specific. Post-treatment levels of CD8 T cells in the TME were higher in subjects with partial response (PR) than stable (SD) or progressive (PD) disease. CD8 (but not CD4) T cell infiltration and the CD8-to-Treg ratio were associated with tumor reduction. TCRseq showed that subjects with PR or SD had greater increase in post-treatment intratumoral clonality than PD (fold change 2.6 [1.9-3.4] vs. 1.1 [0.8-1.5]), implying that tumor-specific clonotypes expanded in subjects with favorable outcome.
Conclusions
NT-I7 and pembro show promising efficacy in cold tumors. This efficacy may be mediated, at least in part, by the ability of NT-I7 to boost CD8 T cell infiltration.
Clinical trial identification
NCT04332653.
Editorial acknowledgement
Legal entity responsible for the study
NeoImmuneTech, Inc.
Funding
NeoImmuneTech, Inc.
Disclosure
A. Naing: Financial Interests, Personal, Advisory Board: CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, Kymab, and STCube Pharmaceuticals; Financial Interests, Institutional, Invited Speaker: NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences; Other, Travel and Accomodation: ARMO BioSciences. S. Ferrando-Martinez: Financial Interests, Personal, Full or part-time Employment: NeoImmuneTech, Inc. A. Wolfarth: Financial Interests, Personal, Full or part-time Employment: NeoImmuneTech, Inc. J.B. Goon: Financial Interests, Personal, Full or part-time Employment, Employed as Research Data Associate: NeoImmuneTech, Inc. M.B. Ware: Financial Interests, Personal, Full or part-time Employment: NeoImmuneTech, Inc. C. Haymaker: Financial Interests, Personal, Other, Participation in an advisory working group: Nanobiotix; Financial Interests, Personal, Other, Session Chair: Society for Immunotherapy of Cancer; Financial Interests, Personal, Other, Stock options as a member of the Scientific Advisory Board: Briacell; Financial Interests, Institutional, Research Grant, Research funding provided to institution: Iovance; Financial Interests, Institutional, Research Grant: Dragonfly, BTG, Sanofi; Non-Financial Interests, Advisory Role, Member of the SAB: Mesothelioma Applied Research Foundation. M. Chaney: Financial Interests, Personal, Full or part-time Employment: Merck and Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck and Co., Inc.; Non-Financial Interests, Member: ASCO, AACR. U.I. Ezeanya: Financial Interests, Personal, Full or part-time Employment: NeoImmuneTech Inc. S. Dhar: Financial Interests, Institutional, Full or part-time Employment: NeoImmuneTech Inc. H. Lee: Financial Interests, Personal, Full or part-time Employment: Geninus, Inc. T. Lee: Financial Interests, Personal, Full or part-time Employment: Geninus, Inc. T. Adebanjo: Financial Interests, Personal, Full or part-time Employment: NeoImmuneTech, Inc. J. Fan: Financial Interests, Personal, Full or part-time Employment: NeoImmuneTech, Inc.; Financial Interests, Personal, Leadership Role, Chief Clinical Officer: NeoImmuneTech, Inc.; Financial Interests, Personal, Stocks/Shares, I have been granted stock options: NeoImmuneTech, Inc.; Financial Interests, Personal, Stocks/Shares, I owned AstraZeneca stock: AstraZeneca; Non-Financial Interests, Personal, Member: ASCO, ESMO. S.H. Yang: Financial Interests, Institutional, Full or part-time Employment, CEO of NeoImmuneTech: NeoImmuneTech; Financial Interests, Institutional, Stocks/Shares: NeoImmuneTech. B.H. Lee: Financial Interests, Personal, Officer, FTE: NeoImmuneTech, Inc.; Financial Interests, Personal, Stocks/Shares: NeoImmuneTech, Inc. R. Kim: Financial Interests, Personal, Advisory Board: Servier, Roche, Taiho, Ipsen, Lilly, Bayer; Financial Interests, Personal, Other, Speaker Bureau: Incyte, Eisai, Exelixis. All other authors have declared no conflicts of interest.