Augmentation of Anti-tumor Immunity by Adoptive T-cell Transfer After Allogeneic Hematopoietic Stem Cell Transplantation

Marie Bleakley; Cameron J Turtle; Stanley R Riddell


Expert Rev Hematol. 2012;5(4):409-425. 

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Expert Commentary

Adoptive immunotherapy is entering a new era where the results of preclinical studies are now being rapidly translated to the clinic. Scientific advances have provided insights into many of the key issues that previously impeded clinical applications and technical developments are improving the feasibility and pace of clinical trials. Key advances in the last few years include the identification of T-cell subsets with the potential for prolonged persistence following adoptive transfer and the technical ability to genetically modify T cells with tumor-targeting TCRs or CARs to confer anti-tumor specificity.

Translation of the next generation of adoptive T-cell therapies to the allogeneic HCT setting using donor T cells of defined specificity and function presents a unique set of challenges and opportunities. In particular, it will be critical to establish platforms for allogeneic HCT that do not require intense immunosuppression to prevent or treat GVHD to provide a hospitable post-HCT environment for immunotherapy, or to endow transferred T cells with resistance to immunosuppressive drugs. The identification of novel minor H antigens that are expressed selectively on hematopoietic cells, including malignant cells, provides a unique opportunity for specific adoptive T-cell therapy that can only be applied after allogeneic HCT. If gene transfer is used to introduce tumor-targeting receptors into donor T cells, it is imperative to know both that the tumor-targeting receptor will not cause on-target toxicity to normal cells and that the endogenous TCR specificities of the engineered cells are not alloreactive to avoid GVHD. These challenges reinforce the need to develop technology that either ensures the elimination of transferred T cells in the case of excessive toxicity or that allows control of the expression of the introduced receptors. These advances will broaden the applicability, efficacy and safety of adoptive immunotherapy in the context of allogeneic HCT, ensuring that the exciting potential of this approach can be realized.