Potential strategies for mitigating CD19 CAR T-cell associated toxicities

From the Gauthier Group, Clinical Research Division

CAR T-cell therapies are a promising treatment modality in hematologic malignancies that rally the immune system to mount a response against cancer cells. In B-cell malignancies, CD19 targeted CAR T-cell treatment is one such therapy, with encouraging responses and remission rates observed in patients. What’s more, complete remission has been sustainable for long periods in some patients, with no additional treatment strategies required. Unfortunately, a dark side to these treatments exists. CD19 CAR-T therapy has been linked to severe treatment related toxicities, including cytokine release syndrome (CRS), a systemic inflammatory state that can rapidly decrease quality of life for patients with side effects including fever and nausea. Additionally, hematologic toxicity from this therapy can cause a decrease in blood cells and is also associated with increased risk of infection. With a goal of finding effective strategies to combat these treatment related toxicities, Drs. Krishna Juluri and Jordan Gauthier at Fred Hutch’s Clinical Research Division retrospectively analyzed clinical trial data from patients with B-cell malignancies treated with CD19 CAR T-cell therapy. Describing the critical need for this research, Dr. Juluri explained how “[..] these toxicities are clinically relevant as they can impact patient quality of life and cost of care due to the need for prolonged growth factor or transfusional support and increased risk of other complications such as infection or bleeding. The underlying factors responsible have not yet been clearly identified, in part due to small study sizes which limited the ability to perform multivariable statistical analysis.” Their work, recently published in Blood Advances, describes an association between CRS and hematopoietic recovery, in addition to revealing a link between cytokines TGFβ-1 and IL-6 with high absolute neutrophil counts and poorer hematopoietic recovery, respectively. “We used high dimensional inference methods to address this toxicity in the largest cohort of patients receiving CD19 CAR T-cell therapy reported to date and identified CRS severity, CRS-associated cytokine levels, and platelet count prior to lymphodepletion as independent factors associated with impaired hematopoietic recovery,” highlighted Dr. Juluri.

For the design of their study, the authors retrospectively accessed clinical data from 173 patients with B-cell malignancies who had received CD19 CAR T treatment as part of enrollment in clinical trials at Fred Hutch. With a view to defining their research strategy, the authors chose absolute neutrophil count, a measure of the number of neutrophils circulating in the blood, and platelet count at 28-days post-treatment as primary measures of hematologic toxicity, as well as utilizing statistical methodology to determine factors that associate with toxicity after therapy. Notably, the authors described a strong prevalence of severe hematologic toxicities including cytopenia (a decrease in blood cells), neutropenia (a decrease in neutrophils) and thrombocytopenia (a decrease in platelets) within their patient population. After assessing absolute neutrophil count and platelet count 28 days after CD19 CAR T-cell treatment, the authors noted no significant difference between patients who were classified as responders and patients who were non-responders to the treatment.

Specific cytokines, IL-6 and TGFβ-1, associate with hematopoietic recovery and hematologic toxicity in B-cell malignancies.
Specific cytokines, IL-6 and TGFβ-1, associate with hematopoietic recovery and hematologic toxicity in B-cell malignancies. This research was originally published in Blood Advances. Juluri KR, Wu V, Voutsinas JM, Hou J, Hirayama AV, Mullane E, Miles N, Maloney DG, Turtle CJ, Bar M and Gauthier J. Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy. Blood Adv (2021) bloodadvances.2020004142, © the American Society of Hematology.

Next, the authors applied statistical method LASSO, an advanced tool for linear regression, allowing for the inclusion of multiple potential variables independently linked to hematopoietic recovery, including age, disease type, CRS grade, and neutrophil and platelet counts. Although the authors did not establish associations between the number of prior treatment regimens or CAR T dose and hematopoietic recovery, as has been previously published, they observed an interesting strong association between high grade CRS and platelet count. Investigating further, they picked several cytokines related to CRS and assessed their ties to hematopoietic recovery in their statistical model. Excitingly, TFGβ-1 was linked to high 28-day absolute neutrophil count and platelet count, with IL-6 documented as a possible player in slower hematopoietic recovery. These findings “raise important questions in how to potentially mitigate this toxicity, either through increased monitoring of cytokines for early detection of potential CRS, early intervention of CRS, and better patient selection,” according to Dr. Juluri.

Going forward, the emphasis is on improving patient selection to identify those who are less likely to suffer hematological toxicities after CAR T-cell treatment. “Our study raises intriguing questions into the role of CRS-related cytokines in promotion or suppression of hematopoiesis, though further studies would need to be done to clearly define the mechanism at play at a cellular level. From a clinical standpoint, our study raises important implications both for patient selection for CAR T-cell therapy and early detection/intervention of CRS. From a methodology/statistics perspective, our study demonstrates the utility of high dimensional inference methods for this type of analysis when multiple covariates and highly correlated covariates are considered,” reiterated Dr. Juluri.

As with most scientific and clinical research, collaboration between disciplines and pooling of expertise is key in supporting studies like this. The University of Washington/Fred Hutch Cancer Consortium “has allowed for collaborations between faculty and researchers across multiple divisions and with research expertise (cellular therapy, immunology, statistics, clinical care) to enable this project to come to fruition,” noted Dr. Juluri.  

This research was supported by grants from the National Institutes of Health, National Cancer Institute, National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases, the Life Science Discovery Fund, the Bezos Family Foundation, the Anderson Family, the Innovation in Cancer Informatics (ICI) Fund, the NHLBI funded National Gene Vector Biorepository at Indiana University, Juno Therapeutics, a University of Washington Division of Hematology Training Grant, and a Cancer Center Support Grant Clinical Scholar award.

UW/Fred Hutch Cancer Consortium members Qian Vicky Wu, David G. Maloney, Cameron J. Turtle and Jordan Gauthier contributed to this work.

Juluri KR, Wu V, Voutsinas JM, Hou J, Hirayama AV, Mullane E, Miles N, Maloney DG, Turtle CJ, Bar M, Gauthier J. Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy. Blood Adv. 2021 Oct 19:bloodadvances.2020004142. doi: 10.1182/bloodadvances.2020004142. Epub ahead of print. PMID: 34666344.