maude et al. blood, 25 june 2015 x volume 125, number 26
TRANSCRIPT
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Maude et al. BLOOD, 25 JUNE 2015 x VOLUME 125, NUMBER 26
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Objectives
• Review B and T cell receptors and rationale behind the CAR T cell
• Review the engineering of CARs • Discuss the clinical results of CARs in hematology malignancy
• Complications and future directions of CAR T cells
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Why CAR’s?• Best of both worlds of the immune system
• B cell specificity• T cell cytotoxicity without presentation
• Form of Adoptive T cell therapy • Synthetically engineered receptors designed to overcome
immune tolerance / tumor evasion • Targets surface molecules in their native confirmation• Engage target independent of antigen presenting cell
(APC) and MHC complex
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Immune Evasion/Tolerance • Tumors decrease T cell response
• Down regulate MHC I, II• Impair Antigen processing • Down regulation of Co-stimulatory molecules (CD28),
Increase PD1 , Increase T regulatory cells • Tolerance
• Unresponsiveness to Ag+ despite exposure to lymphocytes (Anergy)
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Maus et al. Blood 2013
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Ideal CAR Target…• Tumor specific• Universally expressed on only tumor cells• Cell surface molecule • CD 19
• Found on B cell malignant cells (NHL, CLL, ALL, etc)• Expressed on early B cells but NOT stem cells
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Complications of CAR T cells • Cytokine release syndrome (CRS)
• Typically within 5 days and CRP best predictor • Exponential T cell proliferation leads to IL2, IL6, IFN• Can lead to macrophage activation syndrome and
shock / organ failure • Treated with IL6 monoclonal antibodies (Tocilizumab)
• Steroids are second line
Maude et al. Blood May 2015
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Complications of CAR T cells • B Cell aplasia
• Immunoglobulin replacement required to keep Ig > 500
• Encephalopathy • 6/30 patients in CTL019 ALL study
• Unclear pathogenesis• Self limiting• No long term complications• CAR T cells in CSF in all patients
Maude et al. Blood May 2015
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Clinical Data – Hematological Malignancy
• ALL
• CLL
• Chemo-refractory lymphoma
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Maude et al. NEJM 2014
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Results / Complications• 27/30 had CR (90%)
• 6 month EFS 67%• 6 month OS 78%
• All patients had Cytokine release syndrome • 27% had severe CRS
• 13 patients had neurologic deficits ranging from delirium to encephalopathy• 6 patients had severe aphasia, confusion, delirium, seizures and
hallucinations • B cell aplasia
• No circulating B cells by flow cytometry in all patients that persisted for up to one year
Maude et al. NEJM 2014
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Kochenderfer et al. JCO 2015
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Results• DLBCL (n=7)
• 4 CR• 2 PR• 1 SD
• PMBCL (n=4)• 2 CR• 1 SD • 1 Not evaluated
• CLL (n=4)• 3 CR• 1 PR
Kochenderfer et al. JCO 2015
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Lentiviral vector
1.5 x 105 cells/kg
Refractory CLL
Pentostatin day -4
Porter et al. NEJM 2011
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Porter et al. NEJM 2011
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Maus et al. Blood 2015
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Challenges of CAR T cells • Feasibility ($, Institution, etc.)• Training physicians • Relapse of CD19+ or CD19- cells • Defining best CAR
• retrovirus vs. lentivirus • CD28 or 4-IBB as co-stimulatory molecule