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