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Clinical Trial
. 2018 Dec;67(12):1853-1862.
doi: 10.1007/s00262-018-2236-7. Epub 2018 Sep 12.

A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma

Jhanelle E Gray  1 , Alberto Chiappori  2 , Charlie C Williams  2 , Tawee Tanvetyanon  2 , Eric B Haura  2 , Ben C Creelan  2 , Jongphil Kim  3 , Theresa A Boyle  4 , Mary Pinder-Schenck  5 , Farah Khalil  4 , Soner Altiok  4 , Rebecca Devane  6 , David Noyes  7 , Melanie Mediavilla-Varela  7 , Renee Smilee  8 , Emily L Hopewell  8 , Linda Kelley  8 , Scott J Antonia  2
Affiliations
Clinical Trial

A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma

Jhanelle E Gray et al. Cancer Immunol Immunother. 2018 Dec.

Abstract

The GM.CD40L vaccine, which recruits and activates dendritic cells, migrates to lymph nodes, activating T cells and leading to systemic tumor cell killing. When combined with the CCL21 chemokine, which recruits T cells and enhances T-cell responses, additive effects have been demonstrated in non-small cell lung cancer mouse models. Here, we compared GM.CD40L versus GM.CD40L plus CCL21 (GM.CD40L.CCL21) in lung adenocarcinoma patients with ≥ 1 line of treatment. In this phase I/II randomized trial (NCT01433172), patients received intradermal vaccines every 14 days (3 doses) and then monthly (3 doses). A two-stage minimax design was used. During phase I, no dose-limiting toxicities were shown in three patients who received GM.CD40L.CCL21. During phase II, of evaluable patients, 5/33 patients (15.2%) randomized for GM.DCD40L (p = .023) and 3/32 patients (9.4%) randomized for GM.DCD40L.CCL21 (p = .20) showed 6-month progression-free survival. Median overall survival was 9.3 versus 9.5 months with GM.DCD40L versus GM.DCD40L.CCL21 (95% CI 0.70-2.25; p = .44). For GM.CD40L versus GM.CD40L.CCL21, the most common treatment-related adverse events (TRAEs) were grade 1/2 injection site reaction (51.4% versus 61.1%) and grade 1/2 fatigue (35.1% versus 47.2%). Grade 1 immune-mediated TRAEs were isolated to skin. No patients showed evidence of pseudo-progression or immune-related TRAEs of grade 1 or greater of pneumonitis, endocrinopathy, or colitis, and none discontinued treatment due to toxicity. Although we found no significant associations between vaccine immunogenicity and outcomes, in limited biopsies, one patient treated with GMCD40L.CCL21 displayed abundant tumor-infiltrating lymphocytes. This possible effectiveness warrants further investigation of GM.CD40L in combination approaches.

Keywords: Cancer vaccine; Chemokine; Immunotherapy; Non-small cell lung cancer.

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Conflict of interest statement

Scott J. Antonia, MD, Ph.D. is a scientific advisor to CBMG. All other authors have declared no conflicts of interest.

Figures

Fig. 1
Fig. 1
Treatment of Lewis lung cancer mouse models with GM.CD40L plus CCL21 decreases tumor volumes and increases time to progression. Mice were inoculated with tumor cells on day 0 and vaccinated on day 5 and then three more times every 3 to 4 days. Tumor volume was measured. At the end of the study, lymph-node cells and splenocytes were harvested. Time to tumor progression increased significantly in all vaccine-treated mice; however, mice treated with GM.CD40L.CCL21 had a longer time to progression and an overall smaller tumor volume (p = .038)
Fig. 2
Fig. 2
Overall survival and progression-free survival curves. Kaplan–Meier progression-free survival (PFS) curves (a) and overall survival (OS) curves (b) are presented for the intent-to-treat patient population. Blue is GM.CD40L. Purple is GM.CD40L.CCL21
Fig. 3
Fig. 3
Histopathology results from patient 3 (with progressive disease, treated on phase 1 after 3 induction doses on the GM.CD40L.CCL21 vaccine). At week 7, the patient underwent a biopsy of a liver lesion after cycle 1 day 1 of the vaccine. A moderate-to-high infiltration of CD3+ and CD45+ T cells is shown. FNA fine needle aspiration; H&E hematoxylin and eosin
See this image and copyright information in PMC

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