p53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

Clinical Cancer Research - Tập 20 Số 17 - Trang 4459-4470 - 2014
Nicola Hardwick1, Mary Carroll2, Teodora Kaltcheva1, Dajun Qian3, Dean Lim2, Lucille Leong2, Peiguo Chu4, Joseph Kim5, Joseph Chao2, Marwan Fakih2, Yun Yen2, Jonathan Espenschied6, Joshua D.I. Ellenhorn7, Don J. Diamond1, Vincent Chung2
11Division of Translational Vaccine Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California.
22Department of Medical Oncology, City of Hope National Medical Center, Duarte, California.
33Bioinformatics Core Facility, City of Hope National Medical Center, Duarte, California.
44Department of Pathology, City of Hope National Medical Center, Duarte, California.
55Department of Surgical Oncology, City of Hope National Medical Center, Duarte, California.
66Division of Cancer Etiology and Outcomes Research, City of Hope National Medical Center, Duarte, California.
77Cedars-Sinai Medical Center, Los Angeles, California.

Tóm tắt

AbstractPurpose: To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine delivering wild-type human p53 (p53MVA) in patients with refractory gastrointestinal cancers.Experimental Design: Three patients were vaccinated with 1.0 × 108 plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6 × 108 pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in vitro.Results: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T-cell compartment (P = 0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1+ T cells detectable in patients' peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (P = 0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T-cell and antibody responses to the MVA backbone were also apparent.Conclusion: p53MVA was well tolerated and induced robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit. Clin Cancer Res; 20(17); 4459–70. ©2014 AACR.

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Clinical Cancer Research

Tập 20 Số 17

4459-4470

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