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
Notes: Article -- Export Date: 1 March 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Jedd D Wolchok
    854 Wolchok
  2. Taha Merghoub
    321 Merghoub
  3. Melissa P Pulitzer
    167 Pulitzer
  4. Katherine S Panageas
    431 Panageas
  5. Mary Sue Brady
    196 Brady
  6. Charlotte Eielson Ariyan
    124 Ariyan
  7. Jian Hu
    14 Hu
  8. Alexander Rudensky
    139 Rudensky
  9. Achim Jungbluth
    423 Jungbluth
  10. Jianda Yuan
    105 Yuan
  11. Danielle Marie Bello
    30 Bello
  12. Charles H Fisher
    7 Fisher