W192 - Multi-omic Analysis Data from Phase 1 Clinical Trial of CAN-2409 + Valacyclovir in Combination with Nivolumab in High-grade Glioma Demonstrates Systemic Activity After Locally Delivered CAN-2409 Viral Immunotherapy

Patrick Wen – Dana Farber Cancer Institute, Boston, MA; Caroline Duault – Stanford University, Stanford, CA; Edgar Gonzalez-Kozlova – Icahn School of Medicine at Mount Sinai, New York, NY; Tyson Holmes – Stanford University, Stanford, CA; Seunghee Kim-Schulze – Icahn School of Medicine at Mount Sinai, New York, NY; Kai Nie – Icahn School of Medicine at Mount Sinai, New York, NY; Kimberly Argueta – Icahn School of Medicine at Mount Sinai, New York, NY; Jacques Fehr – Icahn School of Medicine at Mount Sinai, New York, NY; Mina Rohani Pichavant – Stanford University, Stanford, CA; Diane Del Valle – Icahn School of Medicine at Mount Sinai, New York, NY; Andrew Gentles – Stanford University, Stanford, CA; Sacha Gnjatic – Icahn School of Medicine at Mount Sinai, New York, NY; Xiaobu Ye – Johns Hopkins University, Baltimore, MD; Len Taing – Dana Farber Cancer Institute, Boston, MA; Jacob Geisberg – Dana Farber Cancer Institute, Boston, MA; Ignacio Ivan Wistuba – MD Anderson Cancer Center, Houston, TX; Cara Haymaker – MD Anderson Cancer Center, Houston, TX; Gheath Al-Atrash – MD Anderson Cancer Center, Houston, TX; Raja Luthra – MD Anderson Cancer Center, Houston, TX; Dzifa Yawa Duose – MD Anderson Cancer Center, Houston, TX; Baili Zhang – MD Anderson Cancer Center, Houston, TX; Jessica Lan – MD Anderson Cancer Center, Houston, TX; Shufang Wang – MD Anderson Cancer Center, Houston, TX; Alexandre Reuben – MD Anderson Cancer Center, Houston, TX; Peixin Jiang – MD Anderson Cancer Center, Houston, TX; Lenika Lopez – Candel Therapeutics, Needham, MA; Susan Bell – Candel Therapeutics, Needham, MA; Andrea Manzanera – Candel Therapeutics, Needham, MA; Audra Caine – Candel Therapeutics, Needham, MA; Jessica Dwyer – Candel Therapeutics, Needham, MA; Sean Lawler – Brown University, Providence, RI; Neeraja Danda – Adult Brain Tumor Consortium, Baltimore, MD; Serena Desideri – Adult Brain Tumor Consortium, Baltimore, MD; L. Burt Nabors – University of Alabama, Birmingham, AL; Stuart Grossman – Adult Brain Tumor Consortium, Baltimore, MD; E. Antonio Chiocca – Dana Farber Cancer Institute, Boston, MA; Paul Peter Tak – Candel Therapeutics, Needham, MA; Holden Maecker – Stanford University, Stanford, CA

Abstract Text: Introduction
CAN-2409/valacyclovir is a locally delivered viral immunotherapy. Preclinical data suggested potential synergy of CAN-2409 with anti-PD1 in an anti-PD1 resistant high-grade glioma (HGG) model. We evaluated the effects of combination CAN-2409/valacyclovir with nivolumab and standard of care (SoC) in HGG patients.

Methods
Forty-one HGG patients were treated in a phase 1 clinical trial (February 2019 - March 2021) with CAN-2409/valacyclovir and SoC plus nivolumab (administered biweekly from week 3 for up to 52 weeks). Comprehensive biomarker analysis on tumor and longitudinal peripheral blood samples was performed by the CIMAC-CIDC Network to characterize local and systemic immune response to treatment.

Results
Survival data were previously reported (SITC 2022). Baseline tumor tissue WES demonstrated frequent in-frame mutations in ARID1B, PAXIP1 and missense mutations in MUC16. Selected combinations of mutations showed statistically significant associations with overall survival. Plasma proteomics and CyTOF revealed activation of a systemic immune response after CAN-2409 monotherapy (week 3) and after co-treatment with nivolumab (week 5): we observed an increase in CD161+CD4+ naïve (p=0.0037, w3), activated CD4+ (p=0.0379, w3; p=0.0011, w5), and CD8+ T cells (p=0.0189, w5). There was also a decrease in immuno-suppressive TIM3+NK cells (p=0.0337, w3; p=0.0324, w5). Combination therapy resulted in expansion of TCR clone density, diversity and clonality in tumors and PBMCs. Imaging analysis of baseline and post-treatment tumor samples by MIBI is ongoing.

Conclusion
Combination treatment with CAN-2409/valacyclovir plus nivolumab and SoC induces immunological changes in both the injected tumor and peripheral blood indicative of activation of an adaptive T cell immune response.