Adoptive cell transfer (ACT) of autologous ex vivo expanded tumor-infiltrating lymphocytes has shown to mediate significant tumor regression in metastatic melanoma. This finding has demonstrated the capacity of endogenous T cells to mount an immune response against and eliminate cancer cells. Two clinically relevant approaches to adoptive cell transfer are ACT of expanded TIL and ACT of gene-modified peripheral blood lymphocytes (PBLs). The former approach consists of isolation of tumor-infiltrating lymphocytes from tumor biopsies, ex vivo expansion and re-infusion after treatment with a lymphodepleting regimen. In the latter, PBLs are engineered to express T-cell receptors (TCRs) recognizing common melanoma tumor antigens. While both approaches have shown different extents of clinical benefit, several limitations hamper clinical efficacy.
T cell specificity, phenotype and differentiation state of ex vivo expanded TIL are largely unknown, while ACT of gene-modified lymphocytes is limited by the use of TCRs recognizing common tumor antigens, which can be differentially expressed between patients. Furthermore, the use of these TCRs is often limited to a handful of HLA types. These factors can lead to reduced therapeutic efficacy and applicability.
Here we aim to compare the tumor control of T cells expressing ‘personalized’ tumor-reactive TCRs and expanded tumor-infiltrating lymphocytes after adoptive cell transfer in a xenograft mouse model. To this end, highly tumor-reactive T cell receptors are isolated from TIL on a per-patient basis. These TCRs are introduced into donor peripheral blood lymphocytes, forming a population of tumor-reactive cells tailored to the patient tumor. These cells are subsequently tested for efficacy in a xenograft mouse model bearing autologous (patient-derived) tumor.
Using the outlined approach, we aim to identify determinants of therapy efficacy. Preliminary results have shown dramatic tumor regression after ACT of patient-specific gene-modified T cells, leading to complete remission of tumors in all treated mice. In contrast, tumors of mice treated with TIL or control T cells did not show significant reduction of tumor burden, when compared to untreated controls.
Citation Format: Lorenzo F. Fanchi, Laura Bies, Ji-Ying Song, Carsten Linnemann, Ton Schumacher. Patient-specific immunotherapy through TCR gene transfer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B044.
- ©2016 American Association for Cancer Research.