CAR T-cell Therapy and Tumor Burden: Implications for Treatment Efficacy

Introduction

Chimeric antigen receptor (CAR) T-cell therapies have revolutionized the treatment landscape for hematologic malignancies. These therapies have shown promising clinical efficacy in various settings. However, a significant number of patients do not respond to CAR T-cell treatments. In a recent review published in JAMA Oncology, researchers aimed to understand the relationship between tumor burden and clinical outcomes in patients undergoing CAR T-cell therapy.

The Impact of Tumor Burden on CAR T-cell Therapy

According to the review, tumor burden plays a critical role in determining the success of CAR T-cell therapy. Large tumors and advanced cancers are associated with increased inflammation and immune dysregulation. These factors negatively affect the production, expansion, antitumor activity, and persistence of CAR T-cell products. Limited tumor infiltration, CAR T exhaustion, heterogeneity or loss of target antigens, and immunosuppressive tumor microenvironments are known factors that contribute to CAR T-cell failure. However, recent studies have highlighted baseline tumor burden as a significant obstacle to durable responses and the safety of CAR T-cell therapy.

Challenges Posed by Tumor Burden

The presence of a large tumor and the associated local and systemic inflammatory and immunologic events pose challenges to CAR T cells. Furthermore, high baseline levels of immunosuppressive traits are linked to both high tumor burden and CAR T-cell therapy failure. Research has shown that large tumors have a more immunosuppressive microenvironment compared to small tumors. Inflammation and immune system dysregulation can negatively impact CAR T cells from manufacturing to persistence upon reinfusion. Chronic inflammation due to tumors can also hinder T-cell manufacturing and contribute to T-cell suppression. High levels of circulating suppressive monocytes and granulocytes, typically associated with advanced cancer stages, can impair CAR T-cell therapy efficacy.

Importance of CAR T Cell-Tumor Ratio

The ratio of targeted CAR T cells to tumor cells is crucial for successful CAR T-cell therapy. However, quantifying this ratio in patients remains a challenge. The review suggests that the ratio of peak CAR T-cell expansion to tumor burden can serve as a prognostic surrogate, but it alone is not sufficient for predicting response.

Barriers in the Tumor Microenvironment

Tumor microenvironment factors, including hypoxia, adenosine, acidic pH, immunosuppressive chemokines, and soluble factors, create barriers for CAR T cells. Patients with leukemia and extramedullary and bulky disease tend to have more complex and stronger inhibitory immune microenvironments compared to those with low tumor burdens. The tumor microenvironment also influences CAR T-cell therapy response in diffuse large B-cell lymphoma.

Impact on Adverse Events

Tumor burden at the time of CAR T-cell treatment is associated with the incidence and severity of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), which are potential life-threatening adverse events. Patients with high tumor burden are more likely to experience severe cases of CRS and ICANS, which have distinct mechanisms.

Solid Tumors and CAR T-cell Therapy

In contrast to hematological malignancies, CAR T-cell therapy has not shown the same efficacy in treating solid tumors. The review highlights that solid tumors and hematological diseases with high tumor burden share poor treatment outcomes. The authors suggest exploring combinatorial strategies such as tumor debulking with surgical resection, radiotherapy, or shifting the use of CAR T-cell therapy to target minimal residual disease as promising areas for further investigation.

Future Directions

The review concludes by emphasizing the need for further research to enhance CAR T-cell efficacy in cases of high tumor burden and unfavorable immune conditions. Novel strategies in CAR T-cell engineering, including gene-editing techniques, hold potential for improving CAR T-cell performance. Investigating CAR T-cell use under conditions of minimal tumor burden or employing CAR T-cell engineering may lead to safety and efficacy improvements against solid tumors.

Conclusion

Understanding the impact of tumor burden on CAR T-cell therapy is crucial for improving treatment outcomes in hematologic malignancies. Large tumors and high tumor burdens contribute to treatment failure by affecting various aspects of CAR T-cell therapy, including expansion, persistence, tumor infiltration, and immunosuppressive microenvironments. While challenges remain in quantifying the CAR T cell-tumor ratio and addressing barriers in the tumor microenvironment, future research in CAR T-cell engineering and combinatorial strategies shows promise for enhancing CAR T-cell therapy efficacy in patients with solid tumors.

Reference:

Ventin M, Cattaneo G, Maggs L, Arya S, Wang X, Ferrone CR. Implications of high tumor burden on chimeric antigen receptor T-cell immunotherapy: a review. JAMA Oncol. Published online November 9, 2023. doi:10.1001/jamaoncol.2023.4504