Vaccine-Induced Intratumoral Lymphoid Aggregates Correlate with Survival Following Treatment with a Neoadjuvant and Adjuvant Vaccine in Patients with Resectable Pancreatic Adenocarcinoma

Abstract

Purpose: Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX). Patients and Methods: Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS). Results: The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS > 24 months to those with OS < 15 months, longer OS was found to be associated with higher density of intratumoral TLA. Conclusions: It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.

Spatio-temporal biodistribution of 89Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model

“…The delayed proliferation or increase in the live cell number of labeled and unlabeled CAR T-cells observed only on day 5 timepoint was expected because Zheng et al . 2020 already demonstrated that the BB3z signaling domain contributed to limited proliferation of CAR T-cells with humanized Lym-1, and replacing BB3z with DAP12 restored expansion capacity in the transduced T-cells 22 . Interestingly, the 89 Zr-oxine labeled CAR T-cells used in the in vivo experiments had higher cell specific activities and showed a transient decrease in %viability on day 1 and an eventual enhanced %viability and live cell count on day 5 compared to unlabeled CAR T-cells.…”

“…Second generation CAR T-cells were constructed following procedures in Zheng et al . 21 , 22 by transducing human primary T-cells with huLym-1-A-BB3z-CAR encoding lentivirus. The CAR sequences consisted of a binding domain (anti huLym-1-A ScFv), hinge and transmembrane domains from human CD8a, and a signaling domain from 4-1BB and CD3ζ (BB3z) (Fig.…”

“…Furthermore, Lym-1 does not cross-react with mouse MHC-II antigen, which prevents it from affecting or influencing tissue biodistribution in the mouse, thus giving us clear results 20 . In our previous studies, we used a metastatic Raji model in which lymphoma cells were administered intravenously and found that the CAR T-cells potently cleared tumor from all sites, including the brain and the lungs, in the NSG mice 21 , 22 . In this study, we chose a subcutaneous model to visualize and quantitate tumor uptake of CAR T-cells at a pre-defined region in the mouse distant from other organs and correlate uptake with the CAR T-cell dose.…”

B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication

“…The authors did not include a control group treated with cyclophosphamide only, and despite they suggested that TLS formation was associated with longer survival; this result was underpowered and biased due to patient selection ( Lutz et al, 2014 ). Recently, Zheng et al (2021) updated the results of this trial after the inclusion of 38 additional patients (87 in total). Combining low dose cyclophosphamide with GVAX promoted worse disease-free survival (arm A × B × C: 18.92 × 8.54 × 5.56 months) and overall survival (34.2 × 15.4 × 16.5) compared to GVAX alone.…”

“…Combining low dose cyclophosphamide with GVAX promoted worse disease-free survival (arm A × B × C: 18.92 × 8.54 × 5.56 months) and overall survival (34.2 × 15.4 × 16.5) compared to GVAX alone. Increased density of intratumoral TLS was associated with longer overall survival ( Zheng et al, 2021 ).…”