Adoptive cell therapy in gynecologic cancers: A systematic review and meta-analysis (309)

Abstract

Objectives: Adoptive cell therapy (ACT) has been studied in recent years with promising results; however, the use of ACT in gynecologic cancers has been limited. We aimed to provide an overview of the use of ACT in gynecologic cancers as they pertain to oncologic outcomes, molecular targets, and toxicity, thereby shedding light on areas requiring further research. Methods: We performed a comprehensive systematic search in Ovid MEDLINE, Ovid EMBASE, Cochrane Library, Web of Science, as well as Clinical Trials.gov, International Clinical Trials Registry, and several associated conference abstracts. Search structures, including MeSH, Emtree, and keywords, were tailored by a medical research librarian specializing in systematic research. Eligible studies included at least one patient with any gynecologic cancer treated with ACT reporting standardized oncologic response or toxicity data. Two principal authors independently screened the abstracts and the resulting fulltext articles. Mann-Whitney U and Kruskal-Wallis tests were performed to examine differences in median objective response rates (ORR, sum of complete response, and partial response). Results: We retrieved 280 unique articles for review. Of these, 27 studies were eligible for the meta-analysis, which comprised 347 patients, including 212 patients with gynecologic cancer (62% ovarian, 33% cervical, 3% endometrial, and 2% other). The types of ACT included were therapies using autologous T cell transfer (33%), T cell receptors (TCR, 23%), tumor-infiltrating lymphocytes (TIL, 20%), chimeric antigen receptor T cells (CAR T, 17%), and NK cells (7%). Median ORR for gynecologic cancers by types of ACT were 49% for TIL, 23% for autologous T cell, 17% for TCR, 14% for NK cell, and 0% for CAR T (p=0.797). Median ORR was numerically higher in studies that included a lymphodepletion regimen (31% vs 9% without, p=0.393). Specific target antigens included HPV16 (28%), folate receptor (17%), mesothelin (17%), NY-ESO-1 (11%), PD1 (6%), MUC1 (5%), and MAGE A3 (5%); median ORR did not vary by antigen (p=0.518). In patients with gynecologic cancers, response rates to ACT included complete response 9%, partial response 20%, stable disease 25%, and progressive disease 34%. By cancer type, the median ORR in cervical and ovarian cancers were 28% and 10%, respectively. Median ORR did not differ between gynecologic and non-gynecologic solid tumors (29% vs 22%, p=0.674). The rates of common adverse events included fever (grade 1/2, 31%; grade 3/4, 1%), hypotension (grade 3/4, 5%), and dyspnea (grade 1/2, 3%). Other common toxicities included fatigue, nausea/vomiting, and hematologic changes. Conclusions: While the sample size is limited, ACT is a promising treatment modality for recurrent gynecologic cancer with an overall ORR of 29% and up to 49% for TIL therapy. Treatment was well tolerated. Further investigation in this field is warranted. Objectives: Adoptive cell therapy (ACT) has been studied in recent years with promising results; however, the use of ACT in gynecologic cancers has been limited. We aimed to provide an overview of the use of ACT in gynecologic cancers as they pertain to oncologic outcomes, molecular targets, and toxicity, thereby shedding light on areas requiring further research. Methods: We performed a comprehensive systematic search in Ovid MEDLINE, Ovid EMBASE, Cochrane Library, Web of Science, as well as Clinical Trials.gov, International Clinical Trials Registry, and several associated conference abstracts. Search structures, including MeSH, Emtree, and keywords, were tailored by a medical research librarian specializing in systematic research. Eligible studies included at least one patient with any gynecologic cancer treated with ACT reporting standardized oncologic response or toxicity data. Two principal authors independently screened the abstracts and the resulting fulltext articles. Mann-Whitney U and Kruskal-Wallis tests were performed to examine differences in median objective response rates (ORR, sum of complete response, and partial response). Results: We retrieved 280 unique articles for review. Of these, 27 studies were eligible for the meta-analysis, which comprised 347 patients, including 212 patients with gynecologic cancer (62% ovarian, 33% cervical, 3% endometrial, and 2% other). The types of ACT included were therapies using autologous T cell transfer (33%), T cell receptors (TCR, 23%), tumor-infiltrating lymphocytes (TIL, 20%), chimeric antigen receptor T cells (CAR T, 17%), and NK cells (7%). Median ORR for gynecologic cancers by types of ACT were 49% for TIL, 23% for autologous T cell, 17% for TCR, 14% for NK cell, and 0% for CAR T (p=0.797). Median ORR was numerically higher in studies that included a lymphodepletion regimen (31% vs 9% without, p=0.393). Specific target antigens included HPV16 (28%), folate receptor (17%), mesothelin (17%), NY-ESO-1 (11%), PD1 (6%), MUC1 (5%), and MAGE A3 (5%); median ORR did not vary by antigen (p=0.518). In patients with gynecologic cancers, response rates to ACT included complete response 9%, partial response 20%, stable disease 25%, and progressive disease 34%. By cancer type, the median ORR in cervical and ovarian cancers were 28% and 10%, respectively. Median ORR did not differ between gynecologic and non-gynecologic solid tumors (29% vs 22%, p=0.674). The rates of common adverse events included fever (grade 1/2, 31%; grade 3/4, 1%), hypotension (grade 3/4, 5%), and dyspnea (grade 1/2, 3%). Other common toxicities included fatigue, nausea/vomiting, and hematologic changes. Conclusions: While the sample size is limited, ACT is a promising treatment modality for recurrent gynecologic cancer with an overall ORR of 29% and up to 49% for TIL therapy. Treatment was well tolerated. Further investigation in this field is warranted.