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Physicians’ Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

These activites are not approved for AMA PRA Category 1 Credit™.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from Juno Therapeutics.

Community Practice Connections™: The Emergence of CAR-T Cell Therapy for Hematologic Malignancies: Moving From Bench to Bedside PER Pulse™ Recap

PER Pulse Recap

PER Pulse™ Recap



1 of 3
PER Pulse Recap

The live continuing medical education activity The Emergence of CAR-T Cell Therapy for Hematologic Malignancies: Moving From Bench to Bedside, presented in conjunction with the 58th American Society of Hematology Annual Meeting & Exposition, featured the following experts describing chimeric antigen receptor (CAR)-T cell therapy: Xiuli Wang, PhD; Stephen J. Forman, MD; Jae Park, MD; Cameron Turtle, MBBS, PhD; and Rebecca A. Gardner, MD. This program featured engaging lectures on the potential of this novel, emerging treatment paradigm to impact the management of patients with hematologic malignancies. This first of 3 PER Pulse™ Recaps reviews the technology of CAR-T cells and how these T cells may be engineered to improve outcomes, as discussed by Dr Forman.

CARs are synthetic molecules composed of a single-chain variable fragment derived from a monoclonal antibody recognizing a tumor antigen and fused to 1 or more T-cell intracellular signaling domains. T cells harvested from the patient are transfected with these CARs and adoptively transferred back into the patient, where they can perform their cytotoxic effector functions.

This therapeutic approach, although still in development, has already demonstrated improvements in clinical benefit through engineering of the CAR molecule. For instance, first-generation CAR molecules used 1 intracellular CAR signaling domain, CD3zeta, which produced only modest efficacy partly because of incomplete T-cell activation. Second-generation CARs overcame this limitation by including CD3zeta and a distinct costimulatory domain; combining signaling through these 2 domains provides the 2 activation signals necessary to fully activate T cells. Efficacy with second-generation T cells has been improved as a result of this change.

Molecular engineering is also being explored to solve other limitations of this therapeutic strategy. For instance, maintaining the persistence of CAR-T cells has been a challenge with current CAR-T cell products. Optimizing the CAR costimulatory domain, engineering CAR-T cells to secrete pro-immune cytokines, and targeting alternate tumor-cell antigens are being considered as ways to overcome this limitation. Safety concerns of CAR-T cell therapy may also be addressed in the future by engineering CAR-T cells to be eliminated in patients experiencing unacceptable toxicity.

For additional commentary about this topic and The Emergence of CAR-T Cell Therapy for Hematologic Malignancies: Moving From Bench to Bedside, please visit www.gotoper.com.



2 of 3
PER Pulse™ Recap

The live continuing medical education activity The Emergence of CAR-T Cell Therapy for Hematologic Malignancies: Moving From Bench to Bedside, presented in conjunction with the 58th American Society of Hematology Annual Meeting & Exposition, featured the following experts describing chimeric antigen receptor (CAR)-T cell therapy: Xiuli Wang, PhD; Stephen J. Forman, MD; Jae Park, MD; Cameron Turtle, MBBS, PhD; and Rebecca A. Gardner, MD. This program featured engaging lectures on the potential of this novel, emerging treatment paradigm to impact the management of patients with hematologic malignancies. This second of 3 PER Pulse™ Recaps discusses the clinical data of CAR-T therapy in B-cell malignancies, as discussed by Drs Turtle and Park.

Of the CD19-expressing B-cell malignancies, acute lymphoblastic leukemia (ALL) appears to demonstrate the highest complete response (CR) rates, consistently exceeding 80% in ALL clinical trials in pediatric and adult populations. Moreover, the vast majority of these complete responders are minimal residual disease-negative, which is a strongly favorable prognostic factor. Novel CAR-T cell approaches currently showing promise within ALL include the use of humanized CAR-T cells, which have activity in patients following relapse after murine CAR-T cell therapy, and CD22-directed CAR-T cells, which have activity in CD19-negative disease.

CD19 CAR-T cells also have activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), although CR rates range from 60% to 80% for NHL and 20% to 40% for CLL. A study in patients with relapsed/refractory diffuse large B-cell lymphoma demonstrated a CR rate of 47%. Despite the lower CR rate in CLL, 1 study showed that CAR-T cells could induce clearance of the bone marrow and prolonged progression-free survival in patients with ibrutinib-refractory CLL, who typically have an extremely poor prognosis.

Because myeloma cells do not express CD19, novel antigens, including B-cell maturation antigen (BCMA), are under investigation for CAR-T cell therapy in patients with multiple myeloma. One phase 1 study presented at the 2016 American Society of Hematology Annual Meeting using BCMA CAR-T cells in patients with heavily pretreated multiple myeloma demonstrated evidence of clinical activity in 6 of 9 patients.

For additional commentary about this topic and The Emergence of CAR-T Cell Therapy for Hematologic Malignancies: Moving From Bench to Bedside, please visit www.gotoper.com.


3 of 3
PER Pulse™ Recap

The live continuing medical education activity The Emergence of CAR-T Cell Therapy for Hematologic Malignancies: Moving From Bench to Bedside, presented in conjunction with the 58th American Society of Hematology Annual Meeting & Exposition, featured the following experts describing chimeric antigen receptor (CAR)-T cell therapy: Xiuli Wang, PhD; Stephen J. Forman, MD; Jae Park, MD; Cameron Turtle, MBBS, PhD; and Rebecca A. Gardner, MD. This program featured engaging lectures on the potential of this novel, emerging treatment paradigm to impact the management of patients with hematologic malignancies. This third of 3 PER Pulse™ Recaps discusses the identification and management of toxicities associated with CAR-T therapy, as discussed by Drs Gardner and Park.

The 2 main toxicities associated with CAR-T cell therapy are cytokine release syndrome (CRS) and neurologic toxicity. The incidences of these CAR-T cell–associated toxicities vary substantially across studies and may be due to differences in CAR-T cell structure, patient populations, disease burden, and toxicity definitions. CRS, which can be life-threatening, is caused by immune activation that results in elevated levels of inflammatory cytokines in the days following CAR-T cell infusion. Symptoms of CRS include fever, hypotension, capillary leak, cardiac dysfunction, renal impairment, hepatic failure, and respiratory failure. Neurologic toxicities associated with CAR-T cells include confusion, delirium, word-finding difficulty, and seizure, but all are generally reversible. Unlike CRS, the mechanism of these neurotoxicities is unknown. Severe neurotoxicity is defined as grade ≥3 nervous system disorders (excluding headache) or grade ≥2 seizures.

The management of severe CRS includes IL-6–targeting tocilizumab in the first line, followed by dexamethasone if resolution does not occur within hours. Managing neurotoxicity is more complicated because the mechanism of its development is unknown, but treatment does involve steroids and tocilizumab. Recent evidence suggests that early intervention of mild toxicities can reduce the rates of severe toxicities due to CAR-T cell therapy.

For additional commentary about this topic and The Emergence of CAR-T Cell Therapy for Hematologic Malignancies: Moving From Bench to Bedside, please visit www.gotoper.com.







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