Chimeric antigen receptor T (CART) cell immunotherapy has been remarkably successful in treating certain relapsed/refractory hematological cancers. However, CART cell therapy is also associated with toxicities which present an obstacle to its wider adoption as a mainstay for cancer treatment. The primary toxicities following CART cell administration are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). New insights into the mechanisms of these toxicities have spurred novel treatment options. In this review, we summarize the available literature on the clinical manifestations, mechanisms, and treatments of CART-associated CRS and ICANS.

CAR-T therapy has shown great success treating blood cancers, but drawbacks include high manufacturing costs and potentially fatal toxicities such as cytokine release syndrome. In this issue of Cell Stem Cell, Li et al. (2018) describe how engineered iPSC-derived NK cells armed with NK-tailored CAR constructs (CAR-iPSC-NK cells) provide better options for anti-cancer immunotherapy.

Despite its revolutionary success in hematological malignancies, chimeric antigen receptor (CAR) T cell therapy faces disappointing clinical results in solid tumors. The poor efficacy has been partially attributed to the lack of understanding in how CAR-T cells function in a solid tumor microenvironment. Hypoxia plays a critical role in cancer progression and immune editing, which potentially results in solid tumors escaping immunosurveillance and CAR-T cell-mediated cytotoxicity. Mechanistic studies of CAR-T cell biology in a physiological environment has been limited by the complexity of tumor-immune interactions in clinical and animal models, as well as by a lack of reliable in vitro models. We have engineered a microdevice platform that recapitulates a three-dimensional tumor section with a gradient of oxygen and integrates fluidic channels surrounding the tumor for CAR-T cell delivery. Our design allows for the evaluation of CAR-T cell cytotoxicity and infiltration in the heterogeneous oxygen landscape of in vivo solid tumors at a previously unachievable scale in vitro.

One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4 and CD8 T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor-infiltrating T cells deep within the immune suppressive TME. Through and studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME. .

Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients.