期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 67, 期 2, 页码 311-325出版社
SPRINGER
DOI: 10.1007/s00262-017-2073-0
关键词
Adoptive transfer; Metastatic melanoma; Clinical trial; Transduced T cells; Immunotherapy; Vitiligo
资金
- National Institute of Health [R43 CA126461, R44 CA126461, R01 CA90873, R01 CA104947, R01 CA104947-S1, P01 CA154778, R01 AI129543-01, R01 AI096879]
- NATIONAL CANCER INSTITUTE [R01CA191317, R44CA126461, P01CA154778, R01CA090873, R43CA126461, R01CA104947] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI129543, R01AI096879] Funding Source: NIH RePORTER
Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4(+) and CD8(+) T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4(+) and CD8(+) T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t(+) cells, then re-activated, and expanded in IL-2 and IL-15. After lymphodepleting chemotherapy, patients were given transduced T cells and IL-2, and were followed for clinical and biological responses. Transduced T cells were detected in the circulation of three treated patients for the duration of observation (42, 523, and 255 days). Patient 1 tolerated the infusion well but died from progressive disease after 6 weeks. Patient 2 had a partial response by RECIST criteria then progressed. After progressing, Patient 2 was given high-dose IL-2 and subsequently achieved complete remission, coinciding with the development of vitiligo. Patient 3 had a mixed response that did not meet RECIST criteria for a clinical response and developed vitiligo. In two of these three patients, adoptive transfer of tyrosinase-reactive TCR-transduced T cells into metastatic melanoma patients had clinical and/or biological activity without serious adverse events.
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