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Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma

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Abstract

Background

While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival remains poor. Immunotherapy may improve outcomes, especially as adjuvant to local therapies. Gene-mediated cytotoxic immunotherapy (GMCI) generates a systemic anti-tumor response through local delivery of an adenoviral vector expressing the HSV-tk gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug. GMCI has demonstrated synergy with standard of care (SOC) in other tumor types. This is the first application in pancreatic cancer.

Methods

Four dose levels (3 × 1010 to 1 × 1012 vector particles) were evaluated as adjuvant to surgery for resectable disease (Arm A) or to 5-FU chemoradiation for locally advanced disease (Arm B). Each patient received two cycles of AdV-tk + prodrug.

Results

Twenty-four patients completed therapy, 12 per arm, with no dose-limiting toxicities. All Arm A patients were explored, eight were resected, one was locally advanced and three had distant metastases. CD8+ T cell infiltration increased an average of 22-fold (range sixfold to 75-fold) compared with baseline (p = 0.0021). PD-L1 expression increased in 5/7 samples analyzed. One node-positive resected patient is alive >66 months without recurrence. Arm B RECIST response rate was 25 % with a median OS of 12 months and 1-year survival of 50 %. Patient-reported quality of life showed no evidence of deterioration.

Conclusions

AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer.

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Abbreviations

AdV-tk:

Adenoviral vector expressing the HSV-thymidine kinase gene

AEs:

Adverse events

APCs:

Antigen-presenting cells

CTCAE:

Common Terminology Criteria for Adverse Events

DLTs:

Dose-limiting toxicities

EUS:

Endoscopic ultrasonography

FACT-Hep:

Functional Assessment of Cancer Therapy-Hepatobiliary

GMCI:

Gene-mediated cytotoxic immunotherapy

LAPC:

Locally advanced pancreatic cancer

MDSCs:

Myeloid-derived suppressor cells

OS:

Overall survival

PanCa:

Pancreatic cancer

PD-1:

Programmed death 1

PD-L1:

Programmed death ligand 1

PFS:

Progression-free survival

PR:

Partial response

PD:

Progressive disease

RECIST:

Response Evaluation Criteria in Solid Tumors

RT:

Radiation therapy

SD:

Stable disease

SOC:

Standard of care

TK:

Thymidine kinase protein from the HSV-thymidine kinase gene

T-regs:

Regulatory T cells

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Acknowledgments

This work was supported in part by the National Cancer Institute at the National Institute of Health [Grant Number R43CA119847] and from The Ohio State University Comprehensive Cancer Center Core Grant from the National Institute of Health [P30CA016058]. The trial is listed in the ClinicalTrials.gov registry, clinical trials identification number NCT00638612.

Conflict of interest

L. K. Aguilar, D. Sanchez, A. G. Manzanera and E. Aguilar-Cordova are employees of Advantagene, Inc. All remaining authors have declared no conflicts of interest related to this study.

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Authors and Affiliations

  1. Advantagene, Inc., Auburndale, MA, 02466, USA

    Laura K. Aguilar, Daniel Sanchez, Andrea G. Manzanera & Estuardo Aguilar-Cordova

  2. James Cancer Hospital/Solove Research Institute, The Ohio State University Wexner Medical Center, 320 W. 10th Avenue, Columbus, OH, 43210, USA

    Lawrence A. Shirley, Jon Walker, Tanios Bekaii-Saab, Gregory B. Lesinski, Benjamin Swanson & Mark Bloomston

  3. City of Hope National Medical Center, Duarte, CA, 91010, USA

    Vincent M. Chung & Howard Marx

  4. Scripps Health, La Jolla, CA, 92037, USA

    Christopher L. Marsh & Walter Coyle

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  1. Laura K. Aguilar
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Correspondence to Mark Bloomston.

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Aguilar, L.K., Shirley, L.A., Chung, V.M. et al. Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma. Cancer Immunol Immunother 64, 727–736 (2015). https://doi.org/10.1007/s00262-015-1679-3

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