Abstract IA18: T cell adoptive therapy for cancer: Translating the science.
Authors: Yang James C. 
Published: August 2014

A variety of immunizations, cytokines and immune checkpoint inhibitors have been used in the effort to marshal an anti-tumor T-cell response capable of rejecting a patient's tumor. Another approach is to activate and expand a population of autologous tumor-reactive T-cells in vitro and administer them back to a patient who has been optimally prepared to support T-cell survival and function. This process, adoptive cell therapy (ACT), allows the use of reagents in vitro that might not be tolerated in vivo, and benefits from manipulations (such as recipient immunosuppression) that can be applied prior to T-cell transfer, to avoid damaging the anti-tumor response. The finding that the tumor infiltrating lymphocytes (TIL) within most human melanomas are tumor reactive has provided the means for studying ACT in cancer patients. Murine models have shown that recipient immunosuppression removes endogenous suppressor cells, induces homeostatic proliferation of transfused T-cells and removes cells that compete for T-cell growth factors. So protocols transferring cultured TIL (along with supportive systemic IL2) into patients with metastatic melanoma who have received a preparative regimen of high-dose cyclophosphamide and fludarabine (Cy-Flu), with or without additional total body irradiation (TBI) have been conducted. In a group of 93 patients (over 80% of whom had visceral metastases and prior IL-2 treatment), the overall response rate was 56% with 21% achieving complete responses. More striking is the fact that with all patients having at least 5-year follow up, 19 of the 20 complete responders have maintained those responses. There were 10 complete responses in 25 patients given Cy-Flu and the highest dose of TBI. There is mounting evidence that the TIL administered can contain multiple specificities, commonly recognizing not only proteins in the pigment production pathway, but also tumor-specific mutations. This experience has shown that ACT is capable of inducing complete responses in patients with disseminated melanoma that appear to have curative potential.

For patients without a tumor-reactive TIL population, it has proven possible to genetically engineer their peripheral blood lymphocytes (PBL) with receptors which recognize their cancer and administer those in lieu of a native TIL population. Retrovirally inserting a T-cell receptor (TCR) cloned from another patient (sharing the appropriate HLA allele) can confer tumor recognition. PBL modified with a TCR against melanocytic lineage antigens (such as MART-1 and gp100) or a tumor-testis antigens (such as NY-ESO-1) have both shown efficacy when given in ACT protocols. In a critical advance, it has been shown that TCR-engineered PBL against NY-ESO-1 not only have activity against metastatic melanoma, but also the NY-ESO-1 positive tumor synovial sarcoma. This conclusively showed that tumors other than melanoma can respond to ACT. In order to further broaden the scope of tumors which can be treated, chimeric antigen receptors consisting of a binding domain derived from a single chain immunoglobulin coupled to the T-cell transduction moiety CD3-zeta have been developed. One such receptor, reactive with CD19 on follicular lymphomas and CLL, has shown activity in refractory patients with those diseases. Ultimately, the real promise from T-cell gene therapy is not in merely redirecting T-cell specificity, but in the intelligent modification of T-cell functions to better effect tumor rejection. One such example in clinical testing is to engineer melanoma TIL to secrete IL-12. This cytokine enhances T-cell secretion of gamma interferon and augments tumor antigen presentation to T-cells. In murine models, this results in a 100-fold increase in T-cell efficacy and does not require the concomitant administration of supportive systemic IL2. A phase I/II protocol testing this concept is underway and early results suggest that not only can some patients respond when unmodified TIL have failed, but objective responses can be seen when many fewer TIL are given with no accompanying IL-2. A host of other functional modifications of T-cells are currently under study and hold out the promise that carefully crafted populations of T-cells can be constructed with gene engineering to induce the durable rejection of a variety of advanced cancers in patients.

Citation Format: James C. Yang. T cell adoptive therapy for cancer: Translating the science. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA18.