T-Cell Therapy Using Interleukin-21-Primed Cytotoxic T-Cell Lymphocytes Combined With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell Persistence and Durable Tumor Regression.
Purpose Peripheral blood-derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs. Patients and Methods Autologous MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells in the presence of interleukin-21 and enriched by peptide-major histocompatibility complex multimer-guided cell sorting. This expeditiously yielded polyclonal CTL lines uniformly expressing markers associated with an enhanced survival potential. In this first-in-human strategy, 10 patients with stage IV melanoma received the MART1-specific CTLs followed by a standard course of anti-CTLA-4 (ipilimumab). Results The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy. Evaluation of best responses at 12 weeks yielded two continuous complete remissions, one partial response (PR) using RECIST criteria (two PRs using immune-related response criteria), and three instances of stable disease. Infused CTLs persisted with frequencies up to 2.9% of CD8+T cells for as long as the patients were monitored (up to 40 weeks). In patients who experienced complete remissions, PRs, or stable disease, the persisting CTLs acquired phenotypic and functional characteristics of long-lived memory cells. Moreover, these patients also developed responses to nontargeted tumor antigens (epitope spreading). Conclusion We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses, highlighting the promise of this strategy.
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Aude G
AG
Chapuis
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Ilana M
IM
Roberts
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
John A
JA
Thompson
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Kim A
KA
Margolin
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Shailender
S
Bhatia
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Sylvia M
SM
Lee
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Heather L
HL
Sloan
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Ivy P
IP
Lai
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Erik A
EA
Farrar
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Felecia
F
Wagener
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Kendall C
KC
Shibuya
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Jianhong
J
Cao
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Jedd D
JD
Wolchok
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Philip D
PD
Greenberg
Aude G. Chapuis, Ilana M. Roberts, Sylvia M. Lee, Heather L. Sloan, Ivy P. Lai, Erik A. Farrar, Felecia Wagener, Kendall C. Shibuya, Jianhong Cao, Philip D. Greenberg, and Cassian Yee, Fred Hutchinson Cancer Research Center; John A. Thompson, Kim A. Margolin, and Shailender Bhatia, Seattle Cancer Care Alliance and University of Washington, Seattle WA; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY.
Cassian
C
Yee
D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000276:immunology*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007378:Interleukins / Q000276:immunology*; D000074324:Ipilimumab / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D012074:Remission Induction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000098546:Interleukin-21
D000074322:Antineoplastic Agents, Immunological; D060908:CTLA-4 Antigen; D007378:Interleukins; D000074324:Ipilimumab; D000098546:Interleukin-21