Adoptive cell transfer (ACT) immunotherapy for patients with metastatic melanoma using autologous tumor infiltrating lymphocytes (TIL) mediated a 56% objective response rate including 20% of patients with durable complete regression ongoing from 6.7 to 10.3 years. Administration of autologous TIL to 9 patients with HPV induced metastatic cervical cancer mediated objective responses in 3 patients including 2 complete regressions that are ongoing beyond a year.
The ideal targets for ACT are the unique mutations that occur in cancers. Using deep exomic sequencing a technique has been developed to identify any cancer mutation, presented on any of the patient's MHC molecules, that gives rise to reactive T cells. We recently reported the successful application of this approach to treat a patient with a metastatic bile duct cancer. Since virtually all cancers contain mutations this approach is now being vigorously studied to expand the current reach of cancer immunotherapy to common epithelial cancers.
Genes encoding conventional alpha-beta T cell receptors (TCR) or chimeric antigen receptors (CAR) can be efficiently transduced into autologous lymphocytes though choosing suitable targets expressed on the cancer is critical to avoid toxicities to essential normal tissues. ACT using CARs to target the CD19 molecule present on normal B cells as well as on the great majority of B cell lymphomas and leukemias was first reported to successfully treat a patient with refractory lymphoma in 2010 in a patient who remains progression-free at five years. Durable complete and partial responses have been seen in patients with chemotherapy refractory indolent and aggressive large B cell lymphomas. Of 9 heavily pretreated patients with large cell lymphomas receiving ACT, 4 patients have had complete regressions, 3 ongoing from 9 to 22 months and 2 additional patients have had partial responses.
Cancer-testes antigens such as NY-ESO-1 and MAGE-A3 are expressed during fetal development and in 10 to 80% of cancers from multiple tissues but are often not expressed in adult normal tissues. ACT targeting NY-ESO-1 resulted in a 67% response rate in 15 treated patients with refractory synovial cell sarcoma and a 53% response rate in 19 patients with melanoma including durable complete regressions. Shared mutations that are unique to an individual cancer type also represent excellent targets for cell transfer immunotherapy and we are conducting a trial using a CAR targeting the EGFRvIII mutation expressed in about 40% of patients with high grade glioblastoma
Citation Format: Steven A. Rosenberg. Curative potential of T-cell immunotherapy for cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA19.
- ©2015 American Association for Cancer Research.