Transient redirection of T cells for adoptive cell therapy with telomerase-specific T helper cell receptors isolated from long term survivors after cancer vaccination

Abstract

Adoptive cell therapy (ACT) with retargeted T cells has produced remarkable clinical responses against cancer, but also serious toxicity. Telomerase is overexpressed in most cancers, but also expressed in some normal cells, raising safety concerns. We hypothesize that ACT with T-helper cell receptors may overcome tumour tolerance, mobilize host immune cells and induce epitope spreading, with limited toxicity. From long term survivors after cancer vaccination, we have isolated telomerase-specific T cell receptors (TCRs) from T-helper cells. Herein, we report the development of transient retargeting of T cells with mRNA-based TCRs. This strategy allows for safer clinical testing and meaningful dose escalation. DP4 is the most common HLA molecule. We cloned two telomerase-specific, DP4-restricted TCRs into the mRNA expression vector pCIpA102, together with the sorter/marker/suicide gene RQR8. Donor T cells were electroporated with mRNA encoding TCR_RQR8. The results showed that both TCR_RQR8 constructs were expressed in >90% of T cells. The transfected T cells specifically recognized the relevant peptide, as well as naturally processed epitopes from a 177aa telomerase protein fragment, and remained functional for six days. A polyfunctional and Th1-like cytokine profile was observed. The TCRs were functional in both CD4+and CD8+recipient T cells, even though DP4-restricted. The findings demonstrate that the cloned TCRs confer recipient T cells with the desired telomerase-specificity and functionality. Preclinical experiments may provide limited information on the efficacy and toxicity of T-helper TCRs, as these mobilize the host immune system. We therefore intend to use the mRNA-based TCRs for a first-in-man trial.

Anti-Cancer Immunotherapies Targeting Telomerase

“…This approach is based on the adoptive transfer of T cells that are genetically manipulated in order to express TCRs with high affinity for a given tumor antigen. TCR-engineered T cells designed to specifically recognize telomerase have been explored, but current data, although encouraging, are limited to pre-clinical experimental settings [108][109][110][111][112].…”

Targeting Telomerase with an HLA Class II-Restricted TCR for Cancer Immunotherapy

“…21 , 22 Notably, we selected the Radium-4 TCR because the original T cell clone also had demonstrated reactivity against autologous ascites cells and thus, a strong sensitivity to endogenous antigen levels, 23 in contrast to the previously reported enhanced hTERT-specific TCRs. 24 , 25 This direct recognition suggests that the hTERT epitope is processed and loaded onto MHC, which is infrequent for MHC class II peptides but attractive in terms of targeting as many solid tumors that also express MHC class II. 26 , 27 We demonstrated here how Radium-4 TCR was efficiently expressed in CD4 + and CD8 + T cells and functional upon specific stimulation, suggesting that although not enhanced, this TCR showed natural high affinity.…”

Multiple Actions of Telomerase Reverse Transcriptase in Cell Death Regulation

“…This cytokine is produced by immune cells, including T and NK cells, and usually inhibits viral replication in host cells [ 147 ]. Thus, an interesting approach is to use immune cells, such as T cells targeting TERT+ cancer cells by the recognition of TERT antigens bound to MHC [ 148 , 149 , 150 , 151 ].…”