The Best of CAR T at the 2024 Tandem Meetings

The Best of CAR T at the 2024 Tandem Meetings Webinar Series, which aired on June 27, 2024, aimed to provide a comprehensive overview of the latest advancements and research in CAR T cell therapy.

Introduction

The Best of CAR T at the 2024 Tandem Meetings Webinar Series, which aired on June 27, 2024, aimed to provide a comprehensive overview of the latest advancements and research in CAR T cell therapy. In this report, we highlight the key points from three expert presentations, focusing on late effects of CAR T cell therapy, the role of the microbiome in relapse, and the implementation of CAR T cell administration in outpatient settings.

Late Effects of CAR T-Cell Therapy

Presented by Dr. Aimee Talleur, Department of Bone Marrow Transplantation and Cellular Therapy St. Jude Children’s Research Hospital

Chimeric antigen receptor (CAR) T cell therapy has been a groundbreaking treatment for cancer that has significantly improved survival rates for pediatric and adolescent young adult (AYA) patients.¹ Unfortunately, the long-term effects of this treatment are not yet well characterized given its relatively recent introduction into clinical practice. As survival rates increase, it will be crucial to understand and manage potential late effects of CAR T cell therapy, particularly for younger recipients.

Dr. Talleur emphasized the importance of a multidisciplinary approach, involving hematologists, immunologists, and psychologists, as well as multi-institutional efforts to establish systematic longitudinal follow-up studies. Current initiatives such as the Pediatric Real World CAR Consortium and the CARnation Consortium are focusing on real-world and investigational CAR T cell products to systematically study late effects, establish standardized longitudinal follow-up studies, and identify biomarkers associated with prolonged toxicities. The PROSPECT and CONQUER studies, for example, are pilot studies designed to evaluate systematic follow-up procedures and assess long-term health outcomes in pediatric CAR T cell therapy recipients. These studies will provide critical data to support future large-scale prospective longitudinal trials.

Among late effects of particular concern are secondary malignancies. Studies have shown that the rate of secondary malignancies is not higher than expected, but this is still a critical area for ongoing research and monitoring, especially among pediatric recipients.² For instance, pooled data from tisagenlecleucel patients indicate a secondary malignancy rate of 2.2%, necessitating long-term follow-up to understand the full spectrum of risks³ and ensure patients are appropriately monitored.

CAR T cell therapy can also potentially impact fertility due to the intensive nature of the treatment. Additionally, bone marrow dysfunction and cytopenias are persistent in a subset of patients, indicating the need for continuous monitoring and optimal intervention strategies.⁴ Infection risks also remain due to variable durations of B cell aplasia and immune reconstitution, highlighting the need for best practices in immune globulin supplementation and vaccination strategies post-therapy.⁵

Overall, there is a clear need for ongoing longitudinal research to comprehensively understand and manage long-term effects of CAR T cell therapy to improve outcomes and quality of life among survivors.

Biology of Relapse After Transplant and Cellular Therapy

Presented by Dr. Melody Smith, Assistant Professor of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine

Dr. Smith's presentation highlighted the impact of the intestinal microbiome on efficacy of CAR T cell therapy.

Microbiome composition plays a critical role in optimizing CAR T cell therapy efficacy.

In a key study, exposure to broader-spectrum antibiotics prior to CAR T cell therapy was associated with decreased overall survival (OS) and progression-free survival (PFS). In a retrospective analysis of 228 patients from Memorial Sloan Kettering and the University of Pennsylvania, those exposed to antibiotics such as piperacillin/tazobactam, imipenem/cilastatin, and meropenem within four weeks of CAR T cell therapy for CD19-positive malignancies had poorer overall survival.⁶ This difference was not seen among patients who received the anaerobe-sparing antibiotic cefepime.

Advanced sequencing techniques, such as 16S ribosomal RNA sequencing and metagenomic shotgun sequencing, have revealed that differences in bacterial composition and metabolic pathways correlate with clinical outcomes. Dr. Smith presented findings on specific bacterial taxa within the gut and their impact on outcomes after CAR T cell therapy. For example, higher abundance of Ruminococcus, Bacteroides, and Faecalibacterium species were associated with complete response at day 100.

Additional studies are exploring the immunologic and regulatory mechanisms by which the microbiome influences CAR T cell efficacy as well as potential interventions to optimize microbiome health and thus increase the likelihood of disease response for CAR T cell recipients.

Outpatient CAR-T in Action

Presented by Dr. David L. Porter, Director, Center for Cell Therapy and Transplant, University of Pennsylvania

Outpatient administration of CAR T cell therapy can increase patient satisfaction, improve their quality of life during treatment, and conserve inpatient resources, which can be particularly critical during times of inpatient bed and staffing shortages. Dr. Porter’s presentation provided a comprehensive framework for implementing outpatient CAR T cell therapy.

At the University of Pennsylvania, over 94% of patients receiving Tisagenlecleucel (Kymriah) for lymphoma were treated as outpatients. These patients had a median age of 66 years, with 96% receiving lymphodepleting chemotherapy as outpatients. The incidence of severe CRS (grade 3-5) was 0%, while 2.8% experienced severe ICANS (grade 3).⁹

Dr. Porter outlined the components of a successful outpatient program, emphasizing the role of a dedicated cellular therapy coordinator who acts as the logistical navigator, financial quarterback, and patient advocate.^10,11 The program also requires multidisciplinary teams, including faculty, fellows, residents, emergency department staff, ICU personnel, and consult services. Robust support systems are essential, involving scheduling, coordination, insurance approval, social services, housing, and data reporting.¹²

Key Aspects of Outpatient Care

Key considerations for outpatient CAR T cell therapy administration include:

Patient Selection: Criteria include stable performance status, proximity to the treatment center, and availability of a dedicated caregiver.

Comprehensive Education: This requires detailed instructions on potential side effects and signs of complications, as well as open lines of communication with the healthcare team.

Regular Monitoring: A robust monitoring system includes frequent outpatient visits, telemedicine check-ins, and the use of wearable devices to track vital signs.

Emergency Protocols: Centers should develop predefined pathways for rapid transition to inpatient care when necessary, with extensive training for staff.

Conclusion

The 2024 Tandem Meetings highlighted critical aspects of CAR T cell therapy, from managing late effects and understanding the microbiome's role in therapy efficacy to implementing outpatient care models. Effective patient management requires a multidisciplinary approach that addresses both the acute and long-term effects of therapy. The microbiome's influence on treatment outcomes further demonstrates the need for personalized health strategies and ongoing research from bench to bedside. Finally, outpatient CAR T cell therapy offers a promising model to enhance patient experience and optimize resource utilization. By integrating these insights, healthcare providers can optimize treatment outcomes and enhance the overall care experience for patients undergoing CAR T cell therapy. With ongoing research and clinical innovations, the future of CAR T cell therapy holds promise for even greater improvements in patient care and survival outcomes.

References

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