Abstract
There is a growing interest in the use of patient-derived T cells for the treatment of various types of malignancies. The expansion of a polyclonal and polyspecific population of tumor-reactive T cells, with a subsequent infusion into the same donor patient, has been implemented, sometimes with positive results. It is not known, however, whether a set of T cells with a single antigen specificity may be sufficient for an effective therapy. To gain more insights in this matter, we used naturally occurring T cells recognizing a retroviral peptide (AH1), which is endogenous in many tumor cell lines of BALB/c origin and which serves as potent tumor rejection antigen. We were able to isolate and expand this rare population of T cells to numbers suitable for therapy experiments in mice (i.e., up to 30 × 106 cells/mouse). After the expansion process, T cells efficiently killed antigen-positive tumor cells in vitro and demonstrated tumor growth inhibition in two syngeneic murine models of cancer. However, AH1-specific T cells failed to induce complete regressions of established tumors. The incomplete activity was associated with a failure of injected T cells to survive in vivo, as only a very limited amount of T cells was found in tumor or secondary lymphoid organs 72 h after injection. These data suggest that future therapeutic strategies based on autologous T cells may require the potentiation of tumor-homing and survival properties of cancer-specific T cells.
Highlights
The recent success of immunotherapy in the oncology field has highlighted the important role the immune system plays in controlling tumor growth
CAR-T cells recognize surface antigens thank to their antibodylike receptors, whereas TCR-transgenic cells are equipped with a native T cell receptor and recognize peptides presented by HLA molecules [2]
The number of living T cells was determined by Trypan Blue exclusion using a hemocytometer, and 3 × 1 06 CFSE-labeled T cells were intravenously injected in BALB/c-bearing established subcutaneous CT26 tumors
Summary
The recent success of immunotherapy in the oncology field has highlighted the important role the immune system plays in controlling tumor growth. Therapeutic proteins like recombinant IL2 or immune checkpoint inhibitors may activate tumor-specific C D8+ cytotoxic T lymphocytes, facilitating the killing of malignant cells in vivo. Chimeric-antigen receptor T cells (CAR-T cells) and T cell receptor-transgenic cells (TCR-transgenic cells) are two examples of genetically engineered T cells [2]. In both cases, T cells are forced to express a synthetic receptor, specific for a tumor-associated antigen (TAA). The extreme paucity of truly tumor-specific surface antigens has so far limited the use of CAR-T cell therapy to certain hematological malignancies, where the toxicity related to the elimination of TAA-positive healthy cells by CAR-T cells (e.g., elimination of CD19positive B cells) is manageable [3]
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