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Gene Expression Profiles Associated with Stable Disease in Metastatic Castration- Resistant Prostate Cancer Patients Treated with ADXS-PSA Immunotherapy Sandra M

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Gene Expression Profiles Associated with Stable Disease in Metastatic Castration- Resistant Prostate Cancer Patients Treated with ADXS-PSA Immunotherapy Sandra M Gene expression profiles associated with stable disease in metastatic castration- resistant prostate cancer patients treated with ADXS-PSA immunotherapy Sandra M. Hayes1, David Balli1, Rachelle E. Kosoff1, Robert G. Petit1, Mark Stein2, Ronald Tutrone3, Anthony Mega4, Manish Agarwal5, Lawrence Fong6, Naomi Haas7 1Advaxis, Inc., Princeton, NJ; 2The Cancer Institute of New Jersey CINJ Rutgers, Inc., New Brunswick, NJ; 3Chesapeake Urology Research Associates; Towson, MD; 4Lifespan Oncology Clinical Re- search, Rhode Island Hospital, Providence, RI; 5Associates in Oncology/Hematology PC, Rockville, MD; 6UCSF University of California San Francisco, San Francisco, CA; 7University of Pennsylvania Abramson Cancer Center; Philadelphia, PA + INTRODUCTION The baseline levels of CD4 T cells were comparable in stable disease and non-stable dis- Figure 7. Functional categories of differentially expressed genes in sta- ease patients, but their levels on treatment were 2-fold higher at week 6 and 2.6-fold ble disease patients on ADXS-PSA treatment • Active immunotherapies, such as ADXS-PSA, are designed to stimulate an antitumor response higher at week 9 in stable disease patients than in non-stable disease patients (P<.001 for T CELL ACTIVATION both time points). Upregulated AND FUNCTION by directly targeting and engaging the immune system. 13% ANTIGEN PROCESSING AND PRESENTATION • ADXS-PSA, a highly attenuated Listeria monocytogenes (Lm)-based immunotherapy that tar- Figure 3. ADXS-PSA treatment increases expression levels of genes identi- 18% ADHESION gets prostate-specific antigen (PSA), is currently being evaluated as a treatment for previous- fying T cells and major T cell subsets in stable disease patients ANTIGEN PROCESSING AND PRESENTATION ly treated metastatic castration-resistant prostate cancer (mCRPC) in the phase 1/2 KEYNOTE NK CELL FUNCTION AUTOPHAGY -046 trial as a monotherapy (Part A, presented here) and in combination with KEYTRUDA® Total T cells CD8+ T cells CD4+ T cells 6% T CELL ACTIVATION AND NKNFSIGNAL -CELLKB SIGNALING FUNCTION TRANSDUCTIONFUNCTIONANTIGENADHESION PROCESSING AND CANCER TESTIS/TUMOR-ASSOCIATED ANTIGENS 1 AUTOPHAGY (pembrolizumab) (Part B, enrolling). INTERFERON SIGNALING0% 6% 0%PRESENTATION6% 175 SD NF-KB SIGNALING CANCER1% TESTIS/TUMOR- 5% 8% 1% CELLULAR FUNCTIONS ASSOCIATED ANTIGENS • Advaxis’ Lm-based immunotherapies act by stimulating innate immunity through multiple 2000 Non-SD CHEMOKINES AND 300 8% CHEMOKINE RECEPTORS CHEMOKINES AND CHEMOKINE RECEPTORS mechanisms including the STING pathway, by reducing the numbers and activities of immuno- 9% 150 * INNATE IMMUNE * FUNCTION CYTOKINES AND COMPLEMENT PATHWAY suppressive cells in the tumor microenvironment, and by inducing the generation of antigen- * 11% CYTOKINE RECEPTORS 2 CELLULAR FUNCTIONS9% specific T cells that infiltrate and destroy the tumor. * 1500 15% CYTOKINES AND CYTOKINE RECEPTORS 200 INNATEDownregulated IMMUNE FUNCTION 3,4 125 • Because of their ability to suppress the immune system, tumors and standard cancer treat- 29% INTERFERON SIGNALING IMMUNE REGULATION 8% CHEMOKINES ANDCANCER TESTIS/TUMOR- ments, such as chemotherapy and radiation therapy, may have an impact on the clinical out- ASSOCIATED ANTIGENS INNATE IMMUNE FUNCTION 1000 CHEMOKINE RECEPTORS8% come of cancer patients receiving active immunotherapies. 5% 100 COMPLEMENT PATHWAY INTERFERON SIGNALING 100 IMMUNECYTOKINES REGULATION AND CYTOKINE • For this reason, we assessed the immune status of previously treated mCRPC patients partici- ExpressionLevels NanoString 8% 1% RECEPTORS NF-KB SIGNALING pating in the KEYNOTE-046 trial. 500 12% 75 CELLULAR FUNCTIONS NK CELL FUNCTION Week 1 Week 3 Week 6 Week 9 Week 1 Week 3 Week 6 Week 9 Week 1 Week 3 Week 6 Week 9 INNATE IMMUNE 15% • Immune status was assessed by profiling and quantifying immune-related gene expression in FUNCTION pre-dose pre-dose pre-dose 29% SIGNAL TRANSDUCTION peripheral blood mononuclear cells (PBMCs) before and after ADXS-PSA treatment. *P<.001 • Part A, the ADXS-PSA dose-determining phase of the KEYNOTE-046 trial, evaluated 3 dose T CELL ACTIVATION AND FUNCTION levels for safety and tolerability. COMPLEMENT PATHWAY OBJECTIVES 8% CYTOKINES AND CYTOKINE • To determine whether the dose level of ADXS-PSA has a bearing on post-treatment immune RECEPTORS 12% • Assess immune status of mCRPC patients who have been previously treated with standard status, we compared the expression levels of T cell-specific genes post-ADXS-PSA treatment lated genes in ADXS-PSA-treated stable disease patients versus ADXS-PSA-treated non- cancer therapies by profiling and quantifying immune-related gene expression in their among the 3 dosing cohorts (Figure 4). PBMCs before and after ADXS-PSA treatment. stable disease patients. Further analysis of the differentially expressed genes within this func- The greatest fold-change above baseline in T cell-specific gene expression levels was ob- tional category revealed that (Figure 8): • Determine whether any gene expression profiles were associated with clinical response to served in the cohort that received the highest dose (1 x 1010 CFU) (P<.05). Interestingly, On ADXS-PSA treatment, stable disease patients expressed significantly higher levels of ADXS-PSA monotherapy. this cohort did not include any patients who achieved clinical activity. genes indicative of M1 macrophages and plasmacytoid dendritic cells (pDCs), both of MATERIALS AND METHODS Figure 4. Highest ADXS-PSA dose affects expression levels of T cell- which have pro-inflammatory antitumor activities.6-10 The M1 macrophage-related genes that were upregulated in stable patients are IFNGR1, CD86, HLA-DR, IL6, IL12B, IL15, and specific genes • The KEYNOTE-046 trial (NCT02325557) is a phase 1/2 evaluation of ADXS-PSA alone (Part CXCL10.6,11,12 The pDC-related genes that were upregulated in stable disease patients are 13 A), and in combination with KEYTRUDA® (pembrolizumab) (Part B), in the treatment of mCRPC. 175 CD86, IL18R1, and IL3RA. 1 x 109 CFU 1 The study design for KEYNOTE-046 trial is summarized in Figure 1. 5 x 109 CFU On ADXS-PSA treatment, stable disease patients expressed significantly lower levels of 1 x 1010 CFU genes indicative of M2 macrophages and myeloid-derived suppressor cells (MDSCs), both 150 160 Figure 1. Study design for KEYNOTE-046 trial SD patients of which have immunosuppressive protumor activities.9,10,14,15 The M2-macrophage-related Non-SD patients genes that were downregulated in stable disease patients are IL13RA, CD163, CD36, 125 Inclusion Criteria: LGAL3, and STAT6.6,11,12 The MDSC-related genes that were downregulated in stable dis- Progressive metastatic castration-resistant prostate 120 All patients ▪ 10,15,16 cancer (mCRPC) on androgen deprivation therapy ease patients are IL13RA1, PTSG2, STAT6, ARG1, ARG2, S100A8, and S100A12. <3 prior systemic treatment regimens, or >1 prior 100 ▪ regimen in the metastatic setting, with chemotherapy Figure 8. Differentially expressed genes involved in innate immune function 80 WEEK 1 WEEK 4 WEEK 7 REPEAT Q12 WEEK CYCLES NanoString ExpressionLevels 75 stable disease vs non-stable disease Downregulated Upregulated Endpoints: Part A Up to PD ▪ Safety/tolerability ADXS-PSA Monotherapy 50 or 2 ▪ RP2D of the 40 ▪ n=12 years combination (Part A) Week 1 Week 3 Week 6 Week 9 Week 1 Week 3 Week 6 Week 9 ▪ Dose escalation (3 dose levels) pre-dose pre-dose ▪ Antitumor activity ADXS-PSA ADXS-PSA ADXS-PSA and progression-free • To determine whether the increases in the levels of T cell-specific genes were associated with Part B Up to PD survival ADXS-PSA + KEYTRUDA® ▪ Peripheral or 2 changes in the state of T cell activation/differentiation, we measured the expression levels of ▪ n=30 immunologic value) years responses genes encoding T cell activation and differentiation markers in PBMCs of stable disease and P KEYTRUDA® KEYTRUDA® KEYTRUDA® KEYTRUDA® non-stable disease patients before and on ADXS-PSA treatment (Figure 5). PD, progressive disease; RP2D, recommended phase 2 dose (adjusted At baseline, stable disease patients expressed: 10 log • Immune-related gene expression was performed on RNA from PBMCs isolated at 4 time significantly higher levels of CXCR3 than non-stable disease patients (P<.001) - points during the first 9 weeks of treatment from mCRPC patients participating in the Part A similar levels of TNFRSF9 (CD137) as non-stable disease patients ADXS-PSA dose-determining stage of the KEYNOTE-046 trial (Figure 2). significantly lower levels of PDCD1 (PD-1), ENTPD1 (CD39), CD48, CD83, TBX21 (Tbet), • The NanoString nCounter PanCancer Immune Profiling Panel was used to quantitate gene IFNG, and GZMB (granzyme B) than non-stable disease patients (P<.001) expression levels. On ADXS-PSA treatment, stable disease patients expressed significantly higher levels of: log2-fold change • Normalized NanoString gene-level counts were compared against NanoString’s immune cell- PDCD1, ENTPD1, and TBX21 than non-stable disease patients at week 3 (P<.001) • The top 5 signaling pathways identified by the IPA software program that represent the 162 specific gene signatures to identify which immune cell types were detected in PBMCs before differentially expressed genes between ADXS-PSA-treated stable disease patients and non- and after ADX-PSA treatment. PDCD1, ENTPD1, CD48, CD83, TNFRSF9, TBX21, and GZMB than non-stable disease patients at week 6 (P<.001). stable disease patients are: • Differential expression analysis was conducted on normalized NanoString count data by
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