TEG011 persistence averts extramedullary tumor growth without exerting off-target toxicity against healthy tissues in a humanized HLA-A*24:02 transgenic mice

Abstract

γδT cells play an important role in cancer immunosurveillance and are able to distinguish malignant cells from their healthy counterparts via their γδTCR. This characteristic makes γδT cells an attractive candidate for therapeutic application in cancer immunotherapy. Previously, we have identified a novel CD8α‐dependent tumor‐specific allo‐HLA‐A*24:02‐restricted Vγ5Vδ1TCR with potential therapeutic value when used to engineer αβT cells from HLA‐A*24:02 harboring individuals. αβT cells engineered to express this defined Vγ5Vδ1TCR (TEG011) have been suggested to recognize spatial changes in HLA‐A*24:02 present selectively on tumor cells but not their healthy counterparts. However, in vivo efficacy and toxicity studies of TEG011 are still limited. Therefore, we extend the efficacy and toxicity studies as well as the dynamics of TEG011 in vivo in a humanized HLA‐A*24:02 transgenic NSG (NSG‐A24:02) mouse model to allow the preparation of a first‐in‐men clinical safety package for adoptive transfer of TEG011. Mice treated with TEG011 did not exhibit any graft‐versus‐host disease‐like symptoms and extensive analysis of pathologic changes in NSG‐A24:02 mice did not show any off‐target toxicity of TEG011. However, loss of persistence of TEG011 in tumor‐bearing mice was associated with the outgrowth of extramedullary tumor masses as also observed for mock‐treated mice. In conclusion, TEG011 is well tolerated without harming HLA‐A*24:02+ expressing healthy tissues, and TEG011 persistence seems to be crucial for long‐term tumor control in vivo.

Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control

“…We previously reported an extensive in vivo safety profile of TEG011 against healthy tissues that express HLA-A*24:02 molecules, in which no significant histological lesions were observed in major organs, including liver, spleen, and intestine ( 40 ). For histopathology analysis, we collected a femur bone marrow section from each treatment group at the end of the study period to further evaluate antitumor efficacy of the new TEG011_CD8α cells ( Figure 4A ).…”

“…TEG011 has been reported to specifically recognize HLA-A*24:02 + malignant cells while sparing the HLA-A*24:02-expressing healthy tissues with the requirement of CD8α co-stimulation ( 34 , 40 ). While TEG011 has shown a favorable efficacy profile in vivo , we only observed in approximately 50% of the mice long-term persistence of CD8 + TEG011 cells, which could be due to the lack of support by antigen-specific CD4 + T cells ( 29 , 40 ). The presence of both tumor-specific CD4 + and CD8 + αβT cells has been reported to significantly improve clinical responses compared to tumor-specific CD8 + αβT cells alone ( 33 ).…”

“…In previous studies, we have shown TEG011 efficacy against HLA-A*24:02-expressing tumor cells in vitro and an extended in vivo safety profile, as well as peripheral persistence of TEG011, where long-term persistence of TEG associated with reduced probability for developing extramedullary solid tumor masses in vivo (34,40). To assess the consequence of the additional expression of TEG011_CD8a, NSG transgenic mice expressing human HLA-A*24:02 (NSG-A24:02) were irradiated, received luciferase-labeled K562 HLA-A*24:02 + cells, and subsequently received two intravenous injections of either mock control TEGLM1_CD8a, TEG011_CD8a, or TEG011 cells.…”

Role of MicroRNA in Inflammatory Bowel Disease: Clinical Evidence and the Development of Preclinical Animal Models

“…Human T cells in engrafted NSG mice are educated on the mouse major histocompatibility complex (MHC). Hence, Shultz and colleagues have developed new stocks of NSG mice that lack murine (MHC) class I and II and transgenically express human MHC HLA class I and class II molecules to enhance human T cell function following engraftment with HSC from human donors [ 65 , 66 , 67 , 68 ]. These mice can be used to study and test regulatory T cell (Treg) therapies for IBD.…”

Characterization and modulation of anti-αβTCR antibodies and their respective binding sites at the βTCR chain to enrich engineered T cells

“…Within this context we have explored a strategy based on the recent development of purified T cells engineered to express a defined gd T cell receptor (TEGs). [19][20][21][22][23][24][25][26][27][28][29] In this strategy we took advantage of the observation that an anti-human abTCR antibody used for the purification of TEGs does not cross-react with gdTCR chains, and it can thereby differentiate between engineered and non-engineered cells. This anti-human abTCR antibody is routinely used to deplete abTCR T cells from apheresis products using CliniMACS depletion before allogeneic stem cell transplantation.…”