Abstract
Simple SummaryCAR-T cell therapy is a new approach to cancer treatment that is based on manipulating a patient’s own T cells such that they become able to seek and destroy cancer cells in a highly specific manner. This approach is showing remarkable efficacy in treating some types of blood cancers but so far has been much less effective against solid cancers. Here, we review the diverse effects of chemotherapy agents on circulating leukocyte populations and find that, despite some negative effects over the short term, chemotherapy can favourably modulate the immune systems of cancer patients over the longer term. Since blood is the starting material for CAR-T cell production, we propose that these effects could significantly influence the success of manufacturing, and anti-cancer activity, of CAR-T cells. Thus, if timed correctly, chemotherapy-induced changes to circulating immune cells could allow CAR-T cells to unleash more effective anti-tumour responses.Adoptive T-cell therapy using autologous T cells genetically modified to express cancer-specific chimeric antigen receptors (CAR) has emerged as a novel approach for cancer treatment. CAR-T cell therapy has been approved in several major jurisdictions for treating refractory or relapsed cases of B-cell precursor acute lymphoblastic leukaemia and diffuse large B-cell lymphoma. However, in solid cancer patients, several clinical studies of CAR-T cell therapy have demonstrated minimal therapeutic effects, thus encouraging interest in better integrating CAR-T cells with other treatments such as conventional cytotoxic chemotherapy. Increasing evidence shows that not only do chemotherapy drugs have tumoricidal effects, but also significantly modulate the immune system. Here, we discuss immunomodulatory effects of chemotherapy drugs on circulating leukocyte populations, including their ability to enhance cytotoxic effects and preserve the frequency of CD8+ T cells and to deplete immunosuppressive populations including regulatory T cells and myeloid-derived suppressor cells. By modulating the abundance and phenotype of leukocytes in the blood (the ‘raw material’ for CAR-T cell manufacturing), we propose that prior chemotherapy could facilitate production of the most effective CAR-T cell products. Further research is required to directly test this concept and identify strategies for the optimal integration of CAR-T cell therapies with cytotoxic chemotherapy for solid cancers.
Highlights
Despite significant advances in treatment, cancer is often an incurable disease
Since blood leukocytes comprise the starting population for the manufacture of chimeric antigen receptor (CAR)-T cells, we propose that these chemotherapyinduced changes could influence the anti-cancer activity of the final CAR-T cell product considerably
Despite the convincing clinical activity of CD19-specific CAR-T-cell therapy, the adoptive transfer of engineered T cells has not been as successful for the treatment of solid cancers [54,55] and the addition of PD-1 inhibition did not further enhance expansion or persistence of GD2-specific CAR-T cells in patients with advanced neuroblastoma [56]
Summary
Despite significant advances in treatment, cancer is often an incurable disease. Empiric or rational combinations of the different modalities of anti-cancer treatment including surgery, radiotherapy, chemotherapy and immunotherapy may be used to enhance the overall therapeutic benefit while minimising the adverse effects of overlapping modes of action [1]. The transient effects of cytotoxic chemotherapy are recognized in the US Food and Drug Administration (FDA) product monographs for the CD19-CAR-T cell therapies, tisagenlecleucel (KymriahTM , Novartis, Basel, Switzerland) and axicabtagene ciloleucel It should be mentioned that a number of chemo-immunotherapy regimens are US FDA-approved as standard first-line treatment for patients with locally advanced or metastatic lung cancer [10,11,12,13]. We discuss how conventional chemotherapy can have substantial and long-lasting effects on the phenotype and frequency of many circulating leukocyte populations, including T cells. Many of these effects are likely to have an overall positive effect on immune function. We conclude by considering how this information could be used to optimise the timing of blood collection for CAR-T cell manufacture, resulting in an enhanced CAR-T cell product and improved patient outcomes
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