Robust antitumor responses result from local chemotherapy and CTLA-4 blockade Journal Article
| Authors: | Ariyan, C. E.; Brady, M. S.; Siegelbaum, R. H.; Hu, J.; Bello, D. M.; Rand, J.; Fisher, C.; Lefkowitz, R. A.; Panageas, K. S.; Pulitzer, M.; Vignali, M.; Emerson, R.; Tipton, C.; Robins, H.; Merghoub, T.; Yuan, J.; Jungbluth, A.; Blando, J.; Sharma, P.; Rudensky, A. Y.; Wolchok, J. D.; Allison, J. P. |
| Article Title: | Robust antitumor responses result from local chemotherapy and CTLA-4 blockade |
| Abstract: | Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been 50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8\+ and CD4\+ T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings into a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and23%partial response rate) and a58% progression-free survival at 1 year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade-based immunotherapy results in a durable response to cancer therapy. |
| Keywords: | cancer survival; clinical article; controlled study; cancer surgery; fatigue; cancer combination chemotherapy; diarrhea; drug efficacy; nonhuman; systemic therapy; treatment duration; gemcitabine; cancer patient; cancer radiotherapy; cancer staging; follow up; anorexia; transcription factor foxp3; cd8+ t lymphocyte; mouse; cytotoxic t lymphocyte antigen 4 antibody; ipilimumab; cancer immunotherapy; low drug dose; melanoma; progression free survival; apoptosis; gene expression; cell infiltration; tumor volume; nausea; myalgia; animal experiment; animal model; cohort analysis; melphalan; antineoplastic activity; in vitro study; arthralgia; pneumonia; prostate cancer; pruritus; rash; alanine aminotransferase; aspartate aminotransferase; t lymphocyte receptor beta chain; blood sampling; cd4+ t lymphocyte; comorbidity; dactinomycin; single drug dose; colitis; innate immunity; upregulation; headache; hypothyroidism; adaptive immunity; dna extraction; immunocompetent cell; peripheral blood mononuclear cell; rna extraction; tumor microenvironment; housekeeping gene; rna isolation; high throughput sequencing; disease burden; human; male; female; article; b16 cell line; tramp-c2 cell line |
| Journal Title: | Cancer Immunology Research |
| Volume: | 6 |
| Issue: | 2 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2018-02-01 |
| Start Page: | 189 |
| End Page: | 200 |
| Language: | English |
| DOI: | 10.1158/2326-6066.cir-17-0356 |
| PROVIDER: | scopus |
| PUBMED: | 29339377 |
| PMCID: | PMC6857638 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2018 -- Source: Scopus |
