A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer

Autor: Lei Zheng, Dwayne L. Thomas, Elizabeth M. Jaffee, Dung T. Le, Julie M. Nauroth, Noah Rozich, Anna Ferguson, Nilofer S. Azad, Jennifer N. Durham, Ana De Jesus-Acosta, Mark Yarchoan, Ross C. Donehower, Arsen Osipov, Adrian Murphy, Robert A. Anders, Christina Rodriguez, Elizabeth D. Thompson, Daniel A. Laheru, Qingfeng Zhu, Chiung Yu Huang
Rok vydání: 2019
Předmět:
0301 basic medicine
Oncology
Male
Cancer Research
Colorectal cancer
medicine.medical_treatment
Phases of clinical research
Pembrolizumab
DNA Mismatch Repair
0302 clinical medicine
Carcinoembryonic antigen
vaccine
Antineoplastic Combined Chemotherapy Protocols
PD-1
Tumor Microenvironment
Original Research
Cancer Biology
Aged
80 and over
biology
Middle Aged
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
GVAX
Progression-Free Survival
3. Good health
Response Evaluation Criteria in Solid Tumors
030220 oncology & carcinogenesis
Female
immunotherapy
Colorectal Neoplasms
medicine.drug
Adult
medicine.medical_specialty
Cyclophosphamide
colorectal cancer
Antibodies
Monoclonal
Humanized
lcsh:RC254-282
Cancer Vaccines
03 medical and health sciences
Internal medicine
medicine
Humans
Radiology
Nuclear Medicine and imaging
Aged
Neoplasm Staging
business.industry
Immunotherapy
medicine.disease
030104 developmental biology
checkpoint inhibitor
biology.protein
business
Zdroj: Cancer Medicine
Cancer Medicine, Vol 9, Iss 4, Pp 1485-1494 (2020)
ISSN: 2045-7634
Popis: Background Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single‐agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor ‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells. Methods We conducted a single‐arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21‐day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression‐free survival, changes in carcinoembryonic antigen (CEA) levels, and immune‐related correlates. Results Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression‐free survival was 82 days (95% confidence interval [CI], 48‐97 days) and the median overall survival was 213 days (95% CI 179‐441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment‐related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre‐ and on‐treatment biopsy specimens showed increases in programmed death‐ligand 1 expression and tumor necrosis in a subset of patients. Conclusions GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response.
Mismatch repair proficient colorectal cancer has been refractory to single‐agent programmed cell death protein 1 inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells. In this single‐arm study, we find that GVAX/Cy plus pembrolizumab results in biochemical responses but not radiographic responses.
Databáze: OpenAIRE
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