Comprehensive Interrogation of Toxicity Profiles Associated with Novel CAR T-cell Constructs

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Learning how to best treat, mitigate, and prevent life-threatening inflammatory toxicities such as cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) was essential to the broad implementation of CAR T-cell therapy. However, as novel antigens started to be targeted and new toxicities emerged, it became clear that ongoing efforts to systematically define these evolving inflammatory toxicities was going to be critical to furthering these therapeutic strategies. Additionally, given the increasing knowledge that minor changes in manufacturing would directly impact clinical outcomes, dedicated study to understand how manufacturing changes would impact outcomes became essential as its own field. Lastly, the ability to predict toxicities would have a tremendous impact on our ability to consider pre-emptive risk mitigation strategies to improve overall outcomes. Having been in the NCI since 2009 and since the inception of the CAR T-cell program in 2012, I have directly provided care for over 200 children and young adults who received a CAR T-cell infusion in the past decade. Additionally, I have directly supported other investigators who are newly embarking on adoptive cell therapies and helped them to overcome novel toxicities experienced. With the privilege of having on-site manufacturing for nearly all our CAR T-cell products which has enabled us to directly study the impact of manufacturing changes on outcomes and with the ability to comprehensively evaluate our patients, a major part of my focus has been on comprehensively studying and understanding the toxicity profiles of patients treated on novel CAR T-cell constructs and using our local observations to make a broader impact in the field of CAR T-cell therapy Specific Aim 1. Evaluate the pathophysiology of hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T-cell infusion. Background: Hemophagocytic lymphohistiocytosis (HLH), as classically defined, is a severe hyperinflammatory syndrome characterized by hyperferritinemia, coagulopathy, hepatic dysfunction and cytopenias amongst a host of other manifestations. While HLH-like toxicities had previously been seen in the context of severe CRS, delayed onset of this emergent inflammatory toxicity was seen less frequently but was associated with severe complications. In the context of our single-center CD22 CAR T-cell trial, my group was the first to describe this toxicity profile. Accomplishments: Though both preclinical and clinical investigations, we comprehensively provided some of the initial insights into the pathophysiology of CAR T-cell associated HLH-like toxicities and the first systematic report characterizing the clinical manifestations. Our efforts provided a foundation for the hypothesis that unmitigated CAR T-cell expansion and suboptimal contraction, in the setting of a relative natural killer (NK)-cell lymphopenia, was potentially causative and aligned with the underlying pathophysiology of primary and secondary HLH, explaining the delayed onset of this toxicity. Furthermore, we demonstrated how IL18 levels correlated with the toxicity profile, and that this could be aggravated by the indiscriminate use of tocilizumab - which has also been seen in the setting of nonmalignant rheumatologic manifestations of macrophage activation syndrome/HLH. Lastly, we described the important role of anakinra, an IL-1 receptor antagonist, in the treatment of these HLH-like manifestations following CAR T-cells. I subsequently lead a multidisciplinary effort to establish consensus diagnostic, grading and treatment approach for this toxicity, that is now called, "Immune effector cell associated HLH-like syndrome" or IEC-HS. Specific Aim 2: Evaluate the impact of manufacturing on CAR T-cell outcomes Background: With on-site manufacturing capability, and in collaboration with the NIH Center for Cellular Engineering, we have conducted extensive investigations in understanding the role of manufacturing on CAR T-cell outcomes. In fact, our group was amongst the first to describe the critical role of CD4/CD8 selection on optimizing CAR T-cell manufacturing and also enhancing CAR T-cell potency. Accomplishments: In addition to the impact of CD4/CD8 selection on both optimizing CAR T-cell manufacturing and impacting toxicity, through ongoing collaborations with the CCE and Taylor Labs, we have also been able to study the impact of cryopreservation on outcomes, and how positive versus negative selection results in distinct cytokine profiles and T cell production. Ongoing collaborations with the Taylor Lab and new investigations with the Altan-Bonnet Lab, are planned and aim to shed insight into CAR T-cell toxicity and approaches to optimize response. Specific Aim 3: Develop risk-scores predictive of severe toxicities and establish novel approaches to effective toxicity mitigation. Background: While extensive work has been done to establish such risk scores in adults with B-cell lymphomas, the applicability of these scores pediatric and young adult patients with B-ALL is limited. Moreover, toxicity mitigation strategies beyond the pre-emptive use of tocilizumab and corticosteroids have not been systematically tested in children and young adults-despite clear scientific rationales to test novel approaches. Accomplishments: Based on our single-center experiences, we have implemented the use of intrathecal hydrocortisone as a very effective and low-risk strategy for the treatment of severe immune effector cell neurotoxicity syndrome (ICANS) and recently published on our experience.We found that in most patients, this led to rapid resolution of ICANS and facilitated the taper of systemic steroids-resulting in the incorporation of this strategy as our institutional approach in the management of severe ICANS. Along these lines, as previously mentioned, we have implemented the utilization of preemptive anakinra to prevent severe IEC-HS on our CD22 CAR T-cell trial and results from this could inform a paradigm shift towards toxicity prevention to improve overall outcomes. Lastly--in collaboration with extramural investigators, we comprehensively explored impact of CAR T-cells on blood counts with a specific focus on B-ALL. This led to development of a novel predictive tool to help clinicians best prepare for outcomes following CAR T-cell therapy. Specific Aim 4: Beyond the aforementioned efforts, my team is also actively engaged in leading multi-center CAR T-cell consortia to better understand how to optimize CAR T-cell therapy in children and young adults. Accomplishments: Through these initiatives, I am involved in leading a study looking at late effects after CAR T-cells (for which we received a Department of Defense Grant) and a patient facing survey evaluating fertility outcomes following CAR T-cell therapy. Both of these initiatives are expected to address unmet needs in the cell therapy field.