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

• Published in: Clinical cancer research Vol. 20; no. 17; pp. 4459 - 4470
• Main Authors: HARDWICK, Nicola R, CARROLL, Mary, YUN YEN, ESPENSCHIED, Jonathan, ELLENHORN, Joshua D. I, DIAMOND, Don J, CHUNG, Vincent, KALTCHEVA, Teodora, DAJUN QIAN, DEAN LIM, LEONG, Lucille, PEIGUO CHU, KIM, Joseph, CHAO, Joseph, FAKIH, Marwan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2014
• Subjects: Aged; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - administration & dosage; Cancer Vaccines - genetics; Cancer Vaccines - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - immunology; Gastrointestinal Neoplasms - prevention & control; Humans; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Pharmacology. Drug treatments; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumor Suppressor Protein p53 - administration & dosage; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - immunology; Tumors; Human; Treatment resistance; Immune response; Gastrointestinal cancer; Malignant tumor; TP53 Gene; Treatment; Digestive diseases; Intestinal disease; Cancer; Gastric disease; Tumor suppressor gene; CD8 T lymphocyte
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-3361

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. Three patients were vaccinated with 1.0×10(8) plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6×10(8) 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. 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. 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.