1. Treating Cancer with
Personalized Cell
Therapies
Thinkfest
Carl H. June, MD
Perelman School of Medicine Philadelphia
University of Pennsylvania
December 1, 2012
2. Personalized “Precision” Therapy
“Physicians consider that, when Philadelphia Chromosome
they have discovered the cause of Discovered by Peter Nowell, Penn
disease, they have also discovered Pathology and Laboratory Medicine
the means of treating it.”
Cicero, 106-43 B.C. Nowell and Hungerford, 1963
4. Targeted Cancer Therapies- A Paradigm Shift
Modern medicine, First Wave = Chemical Blockers
• e.g. aspirin, penicillin and nitrogen mustard
• disadvantage = side effects
Second Wave – Biologicals = Protein Blockers
• e.g. Rituxan®, for lymphoma
• more natural to the body; fewer side effects
• disadvantage = non-permanent and $$ expensive
Third Wave - Immunotherapies and Targeted Therapies
• e.g. engineered cells expressing anti-cancer genes
also “biologicals”, but permanent therapeutic
• $$ cost advantage, if curative
On the horizon ------ Cell Therapies!
5. General Approaches
for T Cell Therapy
Patient Donates Patient
Input Cells (recipient-host)
Host (patient) condition
chemotherapy
± radiotherapy
T cell
transfusion
Optional: genetic engineering
- lentiviral vectors
Expand T cells
Issues
- Customized (patient specific) vaccine
- Blood bank model?
- Market failure…
8. Development of Clinical Scale T Cell
Manufacturing Process
• 1987: Discovery that CD28 is
‘gatekeeper’ for T cell proliferation Bead
addition
• 1993: CD3/CD28 beads first
produced
• 1996: First HIV patients treated Bead
removal
• 2001: First cancer patients
treated
T cell
infusion
11. Pilot Trial Testing CD19 CARs for
Chemotherapy-Resistant/Refractory Leukemia: Status
12 patients Protocol ongoing:
treated to date. 12 patients infused
How do we treat (10 CLL; 2 ALL)
1000s?
Clinical Responses:
NR 3
PR 2
First Patient Dosed: 7/31/2010
CR 7
12. Generalities on First 3 treated patients
All 3 patients had Chronic Lymphocytic Leukemia (CLL)
Very late stage disease
Disease resistant to chemotherapy
Mutations with bad prognosis
3.5-7 pounds of tumor/patient
Each infused CAR T cell killed more than 1000 tumor cells
13.
14. Pediatric CART-19 for Acute Leukemia
PI: Stephan Grupp, MD, PhD
• Subject #1: 7yoF pre-B ALL
• Dx May 2010: standard COG ALL
• Relapse #1: 10/2011
• Relapse #2: 2/2012
• 3/2012: high dose cytoxan/clofaribine:
persistent disease in brain, liver, spleen, kidneys, etc.
• Marrow 4/16/2012: 60% blasts
• CART19 4/17/2012: Dose 3.0x10^9 CD3+ cells
16. Pediatric Patient #1
April 18, 2012 August 29, 2012
Infusion day First day of school
• Status: CR (6 mo+)
17. Goals Over The Next 5 Years
• FDA approval of first gene modified T cell
therapies: CLL, ALL, etc
• Engineered T cells for solid tumors
• Robotic T cell culture: scale up
Here are the cytogenetics, somewhat confusing: INTERPRETATION The bone marrow is largely replaced by a leukemic clone in which the cellshave a modal number of 48 chromosomes per cell. There are three copies ofchromosome 11, and three copies of chromosome 16. There is no evidence byFISH for an MLL rearrangement, other than the extra copy of MLL. FISH studieswere also performed to rule out a cryptic BCR-ABL1 fusion and these studieswere normal. FISH studies did not demonstrate an ETV6-RUNX1 fusion. High resolution array studies were performed, which confirmed deletions in9p and 14q. There was a homozygous deletion of the region containing theCDKN2A locus, due to overlapping deletions in 9p21.3. There was also aheterozygous deletion within the IKAROS locus.Homozygous deletions of the TCR loci in 7p14, 14q11.2 and IGLV region in22q11.2 were also detected, consistent with a clonal leukemia. By report, this patient has recurrent/residual pre B ALL. There was noinformation provided to determine whether the results are consistent with thediagnostic studies. The IKAROS gene deletion would be predictive of a poorprognosis, although there is no evidence at the present time for a BCR-ABL1
