The nutritional impact on CAR therapy

Typically, the immune system continuously eliminates cancer cells. However, some cancer cells can accumulate specific mutations that enable them to evade these natural defense mechanisms (Maude et al., 2015). Cancer immunotherapies have the goal of enhancing the patient's immune system to effectively eliminate cancer cells (Albinger et al., 2021). One approach involves genetic modification of immune cells, particularly T cells and natural killer (NK) cells, to introduce chimeric antigen receptors (CARs). The expression of CARs on T or NK cells enables them to selectively target and destroy cancer cells by recognizing tumor-associated antigens. CAR-T cells have shown promise in eradicating cancer cells when treating hematological diseases (Albinger et al., 2021; Khanmohammadi & Rezaei, 2023). However, limitations and side effects associated with CAR-T cell therapy, such as graft-versus-host disease, neurotoxicity, and cytokine release syndrome, have motivated researchers to explore safer alternative cells like NK cells. Theoretically, CAR-NK cells exhibit a more favorable toxicity profile compared to CAR-T cells, especially in averting adverse effects such as cytokine release syndrome. In the inaugural human clinical trial utilizing CAR-NK therapy to treat CD19-positive lymphoid tumors, 73% of the 11 treated patients exhibited a positive response (Liu et al., 2020). Among these patients, seven (four with lymphoma and three with CLL) achieved complete remission, while one experienced remission of the Richter's transformation component but retained persistent CLL. Notably, these responses manifested rapidly, within 30 days following cell infusion. The administered CAR-NK cells underwent expansion and persisted at lower levels for a minimum of 12 months. While there were no significant adverse effects leading to intensive care unit admission, there were instances of grade 3 and 4 abnormalities observed from the time of CAR-NK cell infusion until day 40. However, it remains unclear whether these abnormalities stemmed from the original disease or the therapy. Another pioneering human study revealed that CAR-NK cells induced no significant harmful effects in three patients with relapsed and refractory acute myeloid leukemia (Tang et al., 2018). Additionally, CAR-NK cells can be manufactured at a significantly reduced cost compared to CAR-T cells, which suggests that, after optimization, they could become widely accessible for the treatment of other cancers. Limited research has delved into the impact of nutrition on CAR-T therapy results. A poster abstract from the European Society for Blood and Marrow Transplantation revealed that 60% of CAR-T patients experienced a weight loss of ≥5%, with 20% enduring a ≥ 10% weight reduction over the course of 4−6 months before and during admission (Ahern et al., 2020). This notably high incidence of malnutrition within this patient group underscores the importance of implementing nutritional screening for all patients before initiating treatment. Additionally, a retrospective study found that 37 out of 132 patients encountered gastrointestinal side effects directly attributable to CAR-T therapy, with 100% experiencing diarrhea, 49% grappling with nausea and vomiting, and 41% reporting abdominal pain (Abu-Sbeih et al., 2019). Another study indicated that CAR-T therapy-induced neurotoxicity was correlated with a weight loss exceeding 10% within 30 days post-treatment in 88 lymphoma patients, underscoring the necessity of dietary support for these patients (Ahern et al., 2023). Consequently, these findings suggest that the nutritional status could potentially serve as a predictive factor for CAR therapy suitability. A suboptimal baseline nutritional status may warrant a period of pre-habilitation, aimed at enhancing nutritional well-being before treatment commencement, ultimately enhancing the prospects of favorable clinical outcomes. At present, there are over 500 CAR-T and 17 CAR-NK cell trials underway worldwide (Albinger et al., 2021). Robust, well-designed studies are essential to investigate the nutritional status both before and after CAR-T therapy, incorporating a prospective longitudinal follow-up. While CAR-NK therapies are still in their early stages, ongoing trials primarily emphasize efficacy and adverse events, often overlooking the nutritional impact. Considering the correlation between malnutrition, weight loss, adverse events, and suboptimal clinical outcomes in cancer patients, it is imperative to prioritize nutritional screening and dietary interventions to mitigate weight loss and adverse events following CAR therapy. This work was supported by USDA/NIFA 2020-67017-30843.