Strategies to Counteract Resistance Mechanisms in CAR+ T-Cell-Based Immunotherapy for Triple-Negative Breast Cancer
Technical Report,01 Sep 2017,31 Aug 2018
Massachusetts General Hospital Boston United States
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The lack of effective therapies for the treatment of metastatic triple negative breast cancer TNBC has prompted us to develop a combinatorial strategy for the treatment of this highly malignant type of breast cancer. In this strategy, the tumor antigen chondroitin sulphate proteoglycan 4 CSPG4 is used as a target, since it is expressed on both differentiated TNBC cells and TNBC cancer initiating cells CICs and has a restricted distribution in normal tissues.Therefore, immunotargeting of CSPG4 is not expected to cause major side effects because of targeting of normal tissues and is expected to eliminate not only differentiated TNBC cells, but also TNBC CICs. According to the cancer stem cell theory, CICs play a major role in disease recurrence and in metastatic spreading. The effector mechanism is represented by T cells transduced with CSPG4-specific chimeric antigen receptor CAR, since i this strategy allows rapid generation of polyclonal T cells with tumor antigen TA-specificity and ii the recognition of tumor cells by CAR T cells does not depend on HLA class I antigen expression by target cells. CAR T cells are combined with strategies which counteract the escape mechanisms utilized by TNBC cells to avoid recognition and destruction by CSPG4 CAR T cells. The escape mechanisms, which are triggered by the changes induced by hypoxia in the tumor microenvironment, include i reduced susceptibility of TNBC cells to the lytic activity of CAR T cells because of the upregulation of antiapoptotic molecules. The latter is caused by the activation of the Sonic Hedgehog Homolog SHH pathway triggered by hypoxia, a hallmark of tumor microenvironment ii the dysfunction of CAR T cells caused by the interaction of PD-1 they express with PD-L1 induced by hypoxia on tumor cells and on non malignant cells present in the tumor microenvironment and iii the reduced viability of CAR T cells because of the unbalanced level of cytokines in the tumor microenvironment.
- Medicine and Medical Research