Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells

Abstract

The goal of cancer immunotherapy is the generation of an effective, stable, and self-renewing antitumor T-cell population. One such approach involves the use of high-affinity cancer-specific T-cell receptors in gene-therapy protocols. Here, we present the generation of functional tumor-specific human T cells in vivo from genetically modified human hematopoietic stem cells (hHSC) using a human/mouse chimera model. Transduced hHSC expressing an HLA-A*0201–restricted melanoma-specific T-cell receptor were introduced into humanized mice, resulting in the generation of a sizeable melanoma-specific naïve CD8 + T-cell population. Following tumor challenge, these transgenic CD8 + T cells, in the absence of additional manipulation, limited and cleared human melanoma tumors in vivo. Furthermore, the genetically enhanced T cells underwent proper thymic selection, because we did not observe any responses against non–HLA-matched tumors, and no killing of any kind occurred in the absence of a human thymus. Finally, the transduced hHSC established long-term bone marrow engraftment. These studies present a potential therapeutic approach and an important tool to understand better and to optimize the human immune response to melanoma and, potentially, to other types of cancer.

Consensus guidelines for the detection of immunogenic cell death

“…95,277 This implies that formally determining whether a given intervention provokes ICD in the human system is complicated. Humanized rodent models, i.e., immunodeficient mice reconstituted with a human immune system, 278 may partially circumvent this issue. However, the interaction between human immune cells and the murine microenvironment may be negatively influenced by inter-species molecular variations that compromise the ability of the former to mount an appropriate immune response.…”

Noninvasive detection of tumor-infiltrating T cells by PET reporter imaging

“…Only a fraction of the CD34 cells are gene modified and a diverse T cell repertoire will develop in vivo (15,32,34). It is possible that the F5-expressing cells may be eliminated by negative selection due to TCR mismatching from endogenous TCR and F5 TCR.…”

“…A modified human bone marrow, liver, thymus (BLT) mouse model was used (32). Animals are made through two independent steps.…”

“…Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) tumor-bearing recipients (these recipients had a rapid decline in peripheral T cells) and (b) a previously described humanized mouse model of HSC adoptive immunotherapy that allows for continuous development of engineered T cells (32). Human HSCs are engineered for TCR expression ex vivo and developed into cytotoxic T cells in vivo.…”

Genetic engineering of hematopoietic stem cells to generate invariant natural killer T cells

“…As an alternative, a TCR-engineered HSC adoptive transfer strategy could overcome these limitations and become clinically applicable. Since its demonstration in mice in the early 2000s, this HSC-engineered T-cell strategy has been widely used to successfully generate both mouse and human antigen-specific conventional αβ T cells in multiple mouse and humanized mouse models (8)(9)(10)(11)(12)(13). Human clinical trials testing this strategy for treating melanoma are also ongoing (14).…”