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Randomized Controlled Trial
. 2021 Mar 1;27(5):1278-1286.
doi: 10.1158/1078-0432.CCR-20-2974. Epub 2020 Dec 4.

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

Lei Zheng #  1   2   3   4   5   6   7 , Ding Ding #  8   3   6 , Barish H Edil  8   2   3   4   7 , Carol Judkins  8   3   4   5 , Jennifer N Durham  8   3   4   5 , Dwayne L Thomas 2nd  8   2   3   5   6 , Katherine M Bever  8   3   4   5   6 , Guanglan Mo  8   3   4   5   6 , Sara E Solt  8   3   4   5 , Jessica A Hoare  8   3   4   5 , Raka Bhattacharya  8   3   4 , Qingfeng Zhu  8   3   4   5   6   7 , Arsen Osipov  8   3   4   5   6 , Beth Onner  8   3   4   5 , Katrina A Purtell  8   3   4   5 , Hongyan Cai  8   3   4   5 , Rose Parkinson  8   3   4   5 , Amy Hacker-Prietz  8   3   4   6   9 , Joseph M Herman  8   3   4   7   9 , Dung T Le  8   3   4   5   6 , Nilofer S Azad  8   3   4   5   6 , Ana M C De Jesus-Acosta  8   3   4   5   6 , Alex B Blair  8   2   3   4   5   6 , Victoria Kim  8   2   3   4   6 , Kevin C Soares  8   2   3   4   7 , Lindsey Manos  8   2   3   4   6   7 , John L Cameron  8   2   3   4   6   7 , Martin A Makary  8   2   3   4   6   7 , Matthew J Weiss  8   2   3   4   6   7 , Richard D Schulick  8   2   3   4   7   10 , Jin He  8   2   3   4   6   7 , Christopher L Wolfgang  8   2   3   4   6   7   11 , Elizabeth D Thompson  8   3   4   6   7   11 , Robert A Anders  8   3   4   5   6   7   11 , Elizabeth Sugar  8   3   4   12 , Elizabeth M Jaffee  8   3   4   5   6   7   11 , Daniel A Laheru  8   3   4   5   6   7
Affiliations
Randomized Controlled Trial

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

Lei Zheng et al. Clin Cancer Res. .

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.

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Figures

Figure 1.
Figure 1.
The CONSORT diagram of the numbers of patients receiving standard of care treatments and vaccine (V) treatments
Figure 2.
Figure 2.. Clinical outcomes for all 87 randomized patients.
A. Kaplan-Meier survival curves of disease-free survival (DFS) of all 87 patients. B. Kaplan-Meier survival curves of overall survival (OS) of all 87 patients
Figure 3.
Figure 3.. Clinical outcomes of 66 evaluable patients.
A. Kaplan-Meier survival curves of disease-free survival (DFS) of 66 patients evaluable for efficacy endpoint. B. Kaplan-Meier survival curves of overall survival (OS) of 66 patients evaluable for efficacy endpoint.
Figure 4.
Figure 4.. Tertiary lymphoid aggregates in PDACs.
A. Hematoxylin and eosin stain of representative untreated PDAC (unvaccinated) and PDAC following vaccine therapy (vaccinated) were shown. Peritumoral and intratumoral lymphoid aggregates were circled in green in lower magnitude images. Selected regions with lymphoid aggregates were also shown in higher magnitude. B. Comparison of the density of intratumoral lymphoid aggregates in PDACs between each two of three arms.
Figure 5.
Figure 5.
Comparison of the density of intratumoral lymphoid aggregates between PDACs with overall survival (OS) less than 15 months and those with OS greater than 24 months.
See this image and copyright information in PMC

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