Transcript (CAR) Products T Cell Receptor

The Role of Immunotherapy for the
Treatment of Hematologic Malignancies
Patrick Stiff MD
Coleman Professor of Oncology
Loyola University Medical Center
708-327-3216
The use of Immune therapy to fight cancer is
not new
• Allogeneic Bone Marrow Transplantation:
adoptive immunotherapy
• Antibodies: rituximab, brentuximab
• Vaccines: anti-HPV, Hepatitis B vaccines
• Dendritic Cell Vaccines
• Engineered T cells
• Chimeric Antigen Receptor T Cells: CAR-T
History of Immunotherapy for
Hematologic Malignancies
Your Immune system is an organ in
your body
The Bone Marrow Plays an Important Role in the Immune System
To invoke the immune system you need a
target
This is called an antigen and is usually on
the surface of the cell
Antigens can be targeted by antibodies or by
cells or in fact by both simultaneously
Schematic of the Immune system
For cancer, T cells do most of the work in
preventing and eliminating disease
Lymph nodes modulate the immune
system
The Ying and Yang of the Immune System
Targets for Immunotherapy are
on the cell surface
In cancer the immune system does not
recognize the specific antigens on the tumor
cells
No response means no cancer cell killing
Immune responses often require both B and T
Lymphocytes
How T-cells can kill cancer
Can the Immune Defect be Repaired: Dendritic Cell
Vaccines
Dendritic Cell Stimulation doe outside the body:re-education
Cancer
Cell
CAR-T Cell Therapies
• Several Platforms/strategies being
developed( U Penn, MSKCC, NCI)
• NCI is working collaboratively with Kite
Pharmaceuticals to develop therapy for
lymphoma and in the future leukemia
using an anti-CD19 CAR-T cell
Figure 5 A schematic of the current approach to anti-CD19 CAR T cell
therapy is shown
Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric
antigen receptors
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46
Chimeric antigen receptors: Clinically target CD19 on B cells (Lymphoma, CLL, ALL)
Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric
antigen receptors
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46
Kite/NCI Study of anti-CD19 CAR in
Relapsed/Refractory B-Cell Malignancies
• Phase 1/2 study investigating safety, feasibility, and efficacy
• Refractory/recurrent disease incurable by standard therapy
• Evolving treatment protocol (conditioning/dosing)
CD19-specific scFv
Co-stimulatory domain: CD28
Essential signaling domain: CD3z of TCR
Streamlined Manufacturing Process for
anti-CD19 CAR T Cells
Apheresis product shipped to
CMO
• Efficient T cell stimulation and
growth without anti-CD3 / antiCD28 beads
Lymphocyte enrichment
T cell activation with anti-CD3 Ab
• Simple, largely closed system
production, amenable to cGMP
operations
Retroviral vector transduction
of CAR gene
• Transportation logistics arranged
T cell expansion
Harvest , cryopreserve product
Ship product; ready for bedside
use
for
6-8multi-center
day process trials
Anti-Tumor Activity Across
Relapsed/Refractory B-cell Malignancies
• 32 patients enrolled (29 evaluable), including largest dataset of
anti-CD19 CAR in lymphoma
Tumor Type
(n evaluable)
Overall Response
Rate
Complete
Response Rate
Any (29)
76%
38%
DLBCL/PMBCL (17)
65%
35%
CLL (7)
86%
57%
Indolent NHL (5)
100%
25%
• 16 patients still in response; 12 ongoing > 1 year
• 3 patients were re-treated after progression; all in ongoing
response (17+ - 52+ months)
Source: S:\CD19\Clinical Development\data\30NOV2014\derived
Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014
Dramatic Response with Anti-CD19 CAR
Before Treatment
Post Treatment
A patient with recurrent
DLBCL post-SCT treated
with anti-CD19 CAR T cells
Ongoing Complete Response
15+ months in a patient with
chemo-refractory PMBCL
Scans from Dr. Rosenberg NCI
Anti-CD19 Treatment Achieves Complete Responses
in Heavily Pretreated Patients with ALL: NCI
experience
Intention-to-Treat
Analysis
ALL
(N=20)
Complete
Response
14 (70%)
MRD negative
Complete
Response
12 (60%)
Allogeneic
Transplant
10 (50%)
Relapse Post
Allogeneic
Transplant
0 (0%)
Lee et al Lancet 2015
78.8%
51.6%
Median follow up = 10 mo
Compelling Evidence of Broad
Anti-Tumor Activity in B Cell Malignancies
•
32 patients enrolled (29 evaluable), largest
dataset of anti-CD19 CAR in lymphoma
•
Response Rate 76% overall, 65% in
DLBCL/PMBCL (n=17)
•
16 patients with ongoing response
•
12 patients with ongoing response over
1 year
•
Emerging AE profile includes:
– Transient cytokine release syndrome
– Reversible neurotoxicity
– B cell aplasia
•
Ongoing clinical studies to optimize cell
number and conditioning regimen
Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014
Figure 4 Regression of adenopathy occurred in a patient with CLL after
treatment with chemotherapy followed by an infusion of anti-CD19 CAR T
cells and IL-2
Parts a, b and c reproduced with permission from American Society of Hematology © Blood 119, 2709–2720 (2012)
Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric
antigen receptors
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46
Figure 3 Eradication of bone marrow and blood CLL cells occurred in a
patient treated with chemotherapy followed by anti-CD19 CAR T cells and IL-2
Reproduced with permission from American Society of Hematology
© Kochenderfer et al. Blood 119, 2709–2720 (2012)
Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric
antigen receptors
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46
Figure 2 Eradication of bone marrow lymphoma and normal B cells occurred
after anti-CD19 CAR T cell infusion
The CD19 and CD79a panels of part a are reproduced with permission from American Society of Hematology
© Kochenderfer et al. Blood 116, 4099–4102 (2010)
Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric
antigen receptors
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46
Study at a Glance KTE-C19-101 Protocol
Key Eligibility Criteria
• Refractory DLBCL, PMBCL, TFL
Phase 1
• Stable disease or progressive
disease as best response to most
DLBCL,
recent chemotherapy containing
PMBCL, TFL
regimen
• Disease progression or recurrence
less than or equal to 12 months of
prior autologous SCT
• ECOG 0-1
Primary Endpoint
• Objective Response Rate
Operations
• Phase 1: First Subject Enrolled by 1stH2015
• Total of approximately 120 pts
• Multi-center study (approximately 25 sites)
Phase 2
Cohort 1:
DLBCL
(n=72)
Cohort 2:
PMBCL and
TFL
(n=40)
DLBCL=Diffuse Large B-cell Lymphoma
PMBCL=Primary Mediastinal B-cell Lymphoma
TFL=Transformed Follicular Lymphoma
ASCT=autologous stem cell transplant
Engineered Autologous T Cell Therapy: 2 Forms
CAR-T vs T-Cell receptor T cells
CAR & TCR Platforms
Redirecting Immune Cells Against Cancer
Chimeric Antigen Receptor (CAR)
Products
Targets
molecules on
the cell surface
T Cell Receptor (TCR) Products
Targets
molecules at or
below the cell
surface
Summary
• We have long understood the importance
of the immune system in preventing and
treating cancer through BMT
• We are now developing methodologies
where our own T-cells can kill and cure
our cancers if they can be modified to do
so
• This therapy of the future is available
today and is impressively curing come
patients