CAR T Therapy: From Bench to Bedside and Back

Release Date: July 15, 2018
Expiration Date: July 14, 2019

Note: This activity is no longer available for credit

Introductory Comments: (Duration: 9 minutes)

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, MD

Presentation: (Duration: 39 minutes)

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

Provided by:

Learning Objectives

• Review clinical data and individual case studies to determine where CAR T-cell therapy might be appropriate in the treatment of adult and pediatric patients with leukemia, lymphoma, and multiple myeloma.

• Discuss the management of cytotoxicity of CAR T-cell therapy.

Target Audience

Hematologists, oncologists, and other members of the healthcare team who treat or manage patients with hematologic malignancies.

Statement of Need

It is critical that clinicians managing patients with acute leukemia and other hematologic malignancies are cognizant of exciting breakthroughs and are also able to integrate recent progress into practice. However, given the overwhelming influx of data, it is no surprise that many hematology professionals face difficulties in identifying the most relevant findings for clinical practice. Hematologists are unable to stay abreast of the latest evidence on investigational agents. Educational programs are thus crucial to address this important professional practice gap.

Faculty

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA
Disclosures: Consultant: Novartis; Grant/Research support and royalties/IPR: Novartis
Stockholder: Tmunity Therapeutics, Inc.

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, Maryland
Disclosures: No relevant financial relationships with a commercial supporter

Permissions

• Slide 3: Complex tumor, host and environmental factors govern the strength and timing of anti-cancer immune responses
  • Reprinted from Immunity, Vol 39/No 1, Chen DS, Mellman I, Oncology meets immunology: the cancer-immunity cycle, pp 1-10, 2013, with permission from Elsevier
• Slide 9: Genes differentially expressed in CART19 cellular infusion products from CLL patients
  • From Fraietta JA, Lacey SF, Orlando EJ, . . . June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018; 24:563-571
• Slide 10: Characterization of CLL CAR T cells in NSG CLL model
  • Same as slide 9
• Slide 15: First adult ALL patient
  • Photos originally published in Kaiser Health News/Photo courtesy of Dr Keith Eaton. Available at: https://khn.org/news/cascade-of-costs-could-push-new-gene-therapy-above-1-million-per-patient/
• Slide 21: Efficient trafficking of CTL019 T Cells to CNS in ALL
  • From N Engl J Med, Grupp SA, Kalos M, Barrett D, . . V. June CH, Chimeric antigen receptor-modified T cells for acute lymphoid leukemia, Volume No 368, pp 1509-1518. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
• Slide 26: Long-term persistence and expression of CTL019 is associated with durable remission in leukemia: Predictive Biomarker
  • From Porter DL, Hwang WT, Frey NV . . . June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7(303):303ra139. Reprinted with permission from AAAS.
• Slide 28: Rapid massive expansion of clonal CART cell population in patient #10
  • Initially published in Fraietta JA, Nobles CL, Sammons MA, . . . June CH, Melenhors JJ. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 2018; 558(7709):307-312
• Slide 29: Mapping CAR integration site in Pt #10
  • Same as slide 28.
• Slide 31: Long-term stable persistence of TET2-deficient CAR T cells in Pt #10
  • Same as slide 28
• Slide 32: Epigenetic and genetic changes uncovered by ATAC-seq in Pt #10
  • Same as slide 28.
• Slide 33: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 34: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 36: CAR T for myeloma: BCMA
  • From Rickert RC, Jellusova J, Miletic AV. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 2011; 244(1):115-33. Reprinted with permission from John Wiley and Sons.
• Slide 38: CAR T for myeloma: Patient #1
  • Photo originally published by UT Southwestern Medical Center. Available at: https://www.utsouthwestern.edu/newsroom/articles/year-2018/wright-car-t.html
• Slide 39: Autoimmunity is the “Achilles’ Heel” of immunotherapy
  • First published in June CH, Warshauer JT, and Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017;23(5):540-7
• Slide 41: Multiplex CRISPR /Cas9 editing: Universal T cells TCR, HLA, PD-1, CTLA-4 and Fas
  • From Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, Zhao Y. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 2017; 8:17002-17011.
• Slide 45: CAR T-cell trials for cancer are now global
  • From June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018; 359:1361-1365. Reprinted with permission from AAAS.