Adoptive Transfer of MART-1 T-Cell Receptor Transgenic Lymphocytes and Dendritic Cell Vaccination in Patients with Metastatic Melanoma

Abstract

Purpose It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short one-week manufacture protocol to determine the feasibility, safety and antitumor efficacy of this double cell therapy. Experimnetal Design A clinical trial (NCT00910650) adoptively transferring MART-1 T cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and re-infused with (n = 10) or without (n = 3) prior cryopreservation. Results 14 patients with metastatic melanoma were enrolled and nine out of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within two weeks of ACT indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared to cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using non-cryopreserved T cells. Conclusion Double cell therapy with ACT of TCR engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

“…The combination of DC vaccination and adoptive T-cell transfer is being tested in multiple trials. These pilot trials have shown the feasibility of the approach, although without full conditioning for adoptive T-cell transfer with lymphocyte-depleting chemotherapy and IL2 infusion in most trials (74)(75)(76). Besides, a variety of chemotherapeutic agents seem to be able to induce immunogenic cell death, making these cells more susceptible for antitumor immunity elicited by DC vaccination (77,78).…”

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL

“…Human serum was removed to minimize risk of viral contamination, process steps were moved from open-to closed-system operations to minimize the risk of microbial contamination, and additional steps were standardized to maximize process consistency. Furthermore, an extended ex vivo expansion of T cells was felt to be potentially detrimental by driving them into exhaustion [27] and thus, a shorter engineered manufacturing process was desirable [28]. The optimized axicabtagene ciloleucel manufacturing method is now able to produce CAR T cells on a large scale in a rapid 6-8 d functionally closed process.…”

PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer

“…is an established procedure (12,13). Targeting cancer-testis antigens (CTAs), including NY-ESO-1, melanoma-associated antigen 3 and glycoprotein 100, using engineered T cells has demonstrated clinical efficacy in the treatment of a number of tumor types (including synovial cell sarcoma, multiple myeloma and melanoma) (10)(11)(12)(13), but has not yet been attempted in breast cancer.…”