Immunologic Signatures of Peripheral Blood T Cells Reveal the Outcome of p53MVA Vaccine and Pembrolizumab Treatment in Patients with Advanced Ovarian Cancer

Article

作者: Dempsey, Shannon ; Ruel, Nora ; Dellinger, Thanh H ; Frankel, Paul ; Diamond, Don J ; Eng, Melissa ; Cristea, Mihaela ; Tinsley, Raechelle ; Kos, Ferdynand J ; Stewart, Daphne

AbstractPurpose:Our previous studies indicated that p53-reactive T cells were associated with clinical benefit in patients with advanced ovarian cancer who were treated with p53-expressing modified vaccinia Ankara (p53MVA) vaccine and gemcitabine chemotherapy. To replace chemotherapy with an approach that will enhance vaccine efficacy and antitumor immunity, we treated patients with p53MVA in combination with PD-1 checkpoint blocker, pembrolizumab. We also attempted to further characterize the activation status of T cells prior to vaccination and during treatment.Experimental Design:Patients received up to three triweekly vaccinations concurrent with pembrolizumab, followed by pembrolizumab monotherapy at 3-week intervals. Correlative studies analyzed peripheral blood T-cell phenotypes and profiles of immune function gene expression.Results:We observed 6/28 (21%) patients with a clinical benefit to therapy, including 3 partial responses (PR) and 3 patients with stable disease (SD) for 6+ months. The median progression-free survival was 1.8 months (95% confidence interval: 1.7–3.8) and median overall survival was 15.1 months (9.4–30.4). Two patients remain progression-free at 28 and 33 months. Of the 18 patients evaluable in correlative studies, 6 were immunologic responders of whom 5 had clinical benefit (3 PR, 2 SD). Immunologic non-responders expressed in pretreatment peripheral blood mononuclear cell samples high levels of mRNA for multiple molecules associated with terminally differentiated T cells.Conclusions:p53MVA/pembrolizumab immunotherapy showed promising antitumor activity in patients who demonstrated functionally competent peripheral blood T cells. Detection of markers of terminally differentiated T cells before treatment may identify patients unlikely to respond to p53MVA/pembrolizumab.Significance:The activity of a combination immunotherapy of p53 vaccine and PD-1 checkpoint blockade in patients with platinum-resistant ovarian cancer was evaluated in a phase II trial. Clinical benefit was correlated with the responsive immune status of patients before and during the treatment, defining potential predictive markers for immune therapy.

2019-03-08·Clinical and Translational Oncology3区 · 医学

Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers

3区 · 医学

Article

作者: Hardwick, N ; Chung, V ; Kos, F J ; Li, D ; Waisman, J ; Frankel, P ; Li, M ; Chao, J ; Zurcher, K ; Diamond, D J ; Yuan, Y

BACKGROUNDVaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors.PATIENTS AND METHODSEleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression.RESULTSWe observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8⁺ T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted.CONCLUSIONWe have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.

2018-03-15·Clinical Cancer Research1区 · 医学

p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy

1区 · 医学

Article

作者: Leong, Lucille ; Cristea, Mihaela ; Kos, Ferdynand ; Eng, Melissa ; Kaltcheva, Teodora ; Tinsley, Raechelle ; Tsai, Weimin ; Kilpatrick, Julie ; Frankel, Paul ; Chung, Vincent ; Diamond, Don J. ; Wilczynski, Sharon ; Ellenhorn, Joshua D.I. ; Ruel, Christopher ; Hardwick, Nicola R. ; Morgan, Robert

AbstractPurpose: To conduct a phase I trial of a Modified Vaccinia Ankara vaccine delivering wild-type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer.Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses.Results: Eleven patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome, and immunologic response. Toxicity: there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients.Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+ T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable. Clin Cancer Res; 24(6); 1315–25. ©2018 AACR.

100 项与 MVA p53 vaccine (Tara Immuno-Oncology) 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
复发性原发性腹膜癌	临床3期	美国	National Cancer Institute	2015-01-01
复发性卵巢癌	临床2期	美国	National Cancer Institute	2018-02-01
复发性铂耐药性输卵管癌	临床2期	美国	National Cancer Institute	2018-02-01
复发性铂耐药性卵巢癌	临床2期	美国	National Cancer Institute	2018-02-01
复发性铂耐药性原发性腹膜癌	临床2期	美国	National Cancer Institute	2018-02-01
肝细胞癌	临床1期	美国	National Cancer Institute	2016-06-14
胰腺腺泡癌	临床1期	美国	National Cancer Institute	2016-06-14
直肠癌	临床1期	美国	National Cancer Institute	2016-06-14
肾细胞癌	临床1期	美国	National Cancer Institute	2016-06-14
三阴性乳腺癌	临床1期	美国	National Cancer Institute	2016-06-14

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASCO2007	临床2期	卵巢癌	21	Subcutaneous peptide admixed with ISA-51 and GM-CSF adjuvants	膚製膚繭淵構築膚衊衊(糧壓鑰範壓鬱遞範齋觸) = 構蓋鬱鹹鏇鑰鏇餘窪鑰憲築齋範壓夢鬱餘膚願 (願醖遞壓淵積鬱鏇製廠 ) 更多	-	2007-06-20
				p53 vaccine (Peptide-pulsed dendritic cells given intravenously)	膚製膚繭淵構築膚衊衊(糧壓鑰範壓鬱遞範齋觸) = 襯繭鹽鏇廠廠齋範廠積憲築齋範壓夢鬱餘膚願 (願醖遞壓淵積鬱鏇製廠 ) 更多