Download CAR T cell lecture 11.25

Maude et al. BLOOD, 25 JUNE 2015 x VOLUME 125, NUMBER 26
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
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
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)
(ASH 2014, Abstract 382, 2014).
Maus et al. Blood 2013
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
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
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
Clinical Data – Hematological Malignancy
• ALL
• CLL
• Chemo-refractory lymphoma
Maude et al. NEJM 2014
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
Kochenderfer et al. JCO 2015
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
Lentiviral vector
1.5 x 105 cells/kg
Refractory CLL
Pentostatin day 4
Porter et al. NEJM 2011
Porter et al. NEJM 2011
Maus et al. Blood 2015
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