Adoptive Cell Transfer Immunotherapy of Cancer

Division Of Basic Sciences - Nci

Investigators

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Abstract

Our laboratory and clinical research efforts have been devoted to studying the cellular immune reactivity against established cancers in experimental animals and in humans and the translation of these findings to the development of effective immunotherapies for patients with cancer. Our early studies demonstrated that the systemic administration of IL-2 could lead to durable objective cancer regressions in patients with metastatic melanoma or metastatic kidney cancer. These clinical studies of IL-2 administration led to studies to identify the immune cells capable of recognizing cancer. We described tumor infiltrating lymphocytes (TIL) in both mice and humans that could be grown from the stroma of solid tumors and have been used to develop adoptive cell transfer therapies. Adoptive cell transfer (ACT) has several theoretical advantages compared to other immunotherapy approaches. In cell transfer therapies highly selected cells with high avidity for recognition of tumor antigens can be activated ex vivo to exhibit anti-tumor effector function, expanded to large numbers, and tested in vitro to identify the exact subpopulations and effector functions that are required for cancer regression in vivo. Perhaps most importantly it is possible to manipulate the host prior to the cell transfer to provide an altered environment for the transferred cells. Naturally occurring tumor infiltrating lymphocytes (TIL) expanded in vitro and administered to melanoma patients resulted in objective responses (RECIST) in 56% of 194 patients including complete regressions in 24% of patients who remain ongoing disease-free with median potential follow up exceeding eight years. To determine the antigens recognized by TIL we developed an approach based on deep exomic and transcriptome sequencing of the cancer and immunologic testing of TIL or peripheral lymphocytes to generate T-cells that recognized immunogenic mutations. TIL from 76 patients with metastatic melanoma recognized 180 random somatic mutations none of which were shared among different melanomas. We next extended these studies to patients with common epithelial cancers that cause 90% of deaths from cancer and showed that 151 of 195 (77%) patients with a variety of human cancer types including esophageal, colorectal, bile duct, gastric, pancreatic, ovarian, cervical and lung cancer contained T-cells that recognized 363 neoantigens all of which were unique except for KRAS (2 patients). Targeting unique cancer mutations has now extended the reach of ACT immunotherapy and was used to mediate objective regressions in selected patients with chemo-refractory metastatic cancers of the bile duct, colon, cervix, and breast. We have begun a series of pilot trials to evaluate cell transfer protocols in patients with chemo-refractory epithelial cancers. No objective responses were seen in 20 patients receiving bulk TIL populations. When TIL were selected for mutation reactivity 3 of 25 (12%) of patients exhibited a response and when pembrolizumab was added 6/26 (23%) of patients responded. The Surgery Branch cell production facility was closed for thirteen months because of an environmental monitoring issue resulting from converting a research laboratory into a GMP laboratory. To correct this problem a new GMP facility has been constructed and the Surgery Branch began utilizing it in February 2022. In the interim considerable progress has been made in laboratory studies. Analysis of prior patients treated with metastatic melanoma utilizing autologous tumor infiltrating lymphocytes resulted in a 56% objective response rate with a 24% complete durable response rate. This study enabled the evaluation of the infusion products in these patients and these studies provided new information concerning the phenotype and function of cells that were associated with tumor regression in humans. Most importantly a "stem like" signature was developed that had a high correlation with antitumor response. This stem like signature was characterized by the lack of expression of CD39 and CD69 molecules. In conjunction with these two phenotypic markers additional stem like genes were identified. Additional studies showed that these stem like lymphocytes persisted far longer than other lymphocytes. It was only the number of the stem like lymphocytes transferred into patients that correlated with antitumor response and not the total number of cells transferred. This information is providing important clues for the application of this treatment to patients with common epithelial cancers. In addition an extensive study was performed in patients with metastatic breast cancer showing that 67% of 42 patients had T cells that recognized their autologous tumor. Thus breast cancers appear to be highly immunogenic and in our initial clinical studies of breast cancer patients 3 of 6 have had RECIST regressions of their metastatic cancer. Autologous T-cells can be used to provide a highly personalized immunotherapy for cancer patients refractory to conventional cancer treatments.