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CAR-T CELLS FOR THE TREATMENT
OF HEMATOLOGIC MALIGNANCIES
Patrick Stiff MD
Loyola University Medical Center
708-327-3216
CAR-T Cells for Hematologic Malignancies
• Why CAR-T cells?
• Our immunity protects us against many pathogens, in particular
viruses and bacteria
• It also helps prevent cancers from developing and helps us in
treating them
• Most important in our cancer surveillance is our T cell lymphocyte
population
• These T Cells are found all over our body: in lymph nodes, spleen
,liver and the blood
• A deficeincy of T cells is seen in most cancers
• T cells in cancer are impotent in most cases-they fail to recognize
and kill cancer cells
• CAR-T cells are manufactured T cells that are engineered to ‘wake-
up’ the immune system to find and kill cancer cells
For cancer, T cells do most of the work in
preventing and eliminating disease
Engineered Autologous T Cell Therapy: 2 Forms
CAR-T Cells and TCR Cells
• CAR: Chimeric Antigen Receptor Cells
• T cells manufactured to directly attach to tumor cells
through specific antigens (normal surface antigens usually
overexpressed in tumor cells)
• Brings the T cells directly to the tumor cell through an
‘unnatural’ attachment through an antigen (tumor cell)
antibody (T cell) connection
• TCR: T Cell Receptor Cells
• T cells manufactured to directly attach to tumor cells
through their normal T cell receptors
• T cell receptors are more specific than antigens on tumor
cells—they are specific to our genetic make-up through our
tissue matching system: the HLA system
• They are capable of recognizing intracellular tumor cell
markers, not just surface markers
Engineered Autologous T Cell Therapy: 2 Forms
CAR-T Cells and TCR Cells
CAR & TCR PlatformsRedirecting Immune Cells Against Cancer
Chimeric Antigen Receptor (CAR)
Products
When infused thesecells Target moleculeson the cell surface which lead to theirdeath
Virus carries a signal into T cells that
codes for a new antibody-derived
binding domain on the cell surface that
recognizes certain normal antigens
that are expressed in tumor cells.
Again T cells are expanded in culture
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 1 Chimeric antigen receptors
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 5 A schematic of the current approach to anti-CD19 CAR T cell
therapy is shown
CAR-T Cells
Effective in:
1. Acute Lymphoid Leukemia: B-Cell type
2. Non-Hodgkin’s Lymphoma: B-Cell type
3. Chronic Lymphocytic Leukemia
4. Multiple Myeloma
Early CD19-specific-CAR T-cell therapy outcomes in patients
with B-ALL (Acute Lymphoid Leukemia)
Jackson, H. J. et al. (2016) Driving CAR T-cells forward
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.36
Anti-CD19 Treatment Achieves Complete Responses in Heavily
Pretreated Patients with ALL: NCI experience-2015
Lee et al Lancet 2015
Intention-to-Treat
Analysis
ALL
(N=20)
Complete
Response 14 (70%)
MRD negative
Complete
Response
12 (60%)
Allogeneic
Transplant10 (50%)
Relapse Post
Allogeneic
Transplant
0 (0%)
78.8%
51.6%
Median follow up = 10 mo
NEJM: 2/1/18
NEJM: 2/1/18
The rate of relapse-free
survival among patients with
a response to treatment was
80% (95% CI, 65 to 89) at 6
months and 59% (95% CI, 41
to 73) at 12 months. Among
patients with complete
remission, 17 had a relapse
before receiving additional
anticancer therapy. Relapse
also occurred in 3 patients
who proceeded to receive
new cancer therapy for the
emergence of minimal
residual disease
Kite/NCI Study of anti-CD19 CAR in
Relapsed/Refractory B-Cell Lymphomas
• 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• Efficient T cell stimulation and
growth without anti-CD3 / anti-CD28 beads
• Simple, largely closed system production, amenable to cGMP operations
• Transportation logistics arranged for multi-center trials
Apheresis product shipped to
CMO
Lymphocyte enrichment
Retroviral vector transductionof CAR gene
T cell expansion
Harvest , cryopreserve product
T cell activation with anti-CD3 Ab
Ship product; ready for bedside
use
6-8 day process
Anti-Tumor Activity Across
Relapsed/Refractory B-cell Malignancies
• 32 patients enrolled (29 evaluable), including largest dataset of anti-
CD19 CAR in lymphoma
• 16 patients still in response; 12 ongoing > 1 year
• 3 patients were re-treated after progression; all in ongoing response
(17+ - 52+ months)
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%
Source: S:\CD19\Clinical Development\data\30NOV2014\derived
Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014
Scans from Dr. Rosenberg NCI
Before Treatment Post Treatment
Ongoing Complete Response
15+ months in a patient with
chemo-refractory PMBCL
A patient with recurrent
DLBCL post-SCT treated
with anti-CD19 CAR T cells
Dramatic Response with Anti-CD19 CAR
Updated Data from US Multicenter Trial:
2017
DLBCL: Diffuse Large B cell Lymphoma
TFL: transformed follicular lymphoma
PMBCL: Primary Mediastinal B cell
lymphoma
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
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)
Several centers in Chicago continue exploring CAR-T cells for Lymphoma
and B-Cell ALL in Research Trials
Loyola continues to move forward with Immunotherapy trials by participating
in following trials-
• ZUMA 2 - Relapsed/Refractory Mantle Cell Lymphoma and
• ZUMA 3- Adult Relapsed/Refractory B-precursor Acute Lymphoblastic
Leukemia.
The FDA has licensed however CAR-T cells for the commercial use in:
• Pediatric ALL (Novartis—August 2017)
• Adult Diffuse Aggressive NHL (Kite—November 2017 and Novartis—May
2018)
• These can not be administered at community centers—currently approved
by the companies for only FACT approved BMT centers
CAR-T Cell Availability: ALL and
Lymphoma
BCMA CAR-T Cells in Multiple Myeloma
Immunotherapy for Multiple Myeloma
NCI’s first BCMA CAR-T trial Results
1. At low doses—minor
responses
2. At higher doses: 3 million
cells/kg more impressive
responses including complete
remissions in patients with
drug refractory disease
3. Toxicities are dose related
however
4. In some prolonged
suppression of blood counts
was seen
5. Relapses do occur
BlueBird Phase I Data: 2017
Bluebirds December 2017 BCMA Car-T Update
High Response Rates for BCMA CAR-T in Myeloma
Downsides of CAR-T Cells
• Pediatric ALL Study:
NEJM: 2/1/18
Downsides of CAR-T Cells• Pediatric ALL Study:
Cytokine Release Syndrome: fever, drop in blood pressure,
SOB—due to the reaction of CAR-T with tumor cells
• The cytokine release syndrome occurred in 58 of 75 patients (77%);
• the median time to onset was 3 days (range, 1 to 22), and the median
duration was 8 days (range, 1 to 36).
• A total of 35 of 75 patients (47%) were admitted to the intensive care
unit (ICU)for median stay of 7 days (range, 1 to 34).
• 19 patients (25%) were treated with high-dose vasopressors,
• 33 (44%) received oxygen supplementation,
• 10 (13%) received mechanical ventilation,
• 7 (9%) underwent dialysis
• 28 (37%) received tocilizumab for management of the cytokine
release syndrome.
NEJM: 2/1/18
Downsides of CAR-T Cells• Pediatric ALL Study:
• Neurotoxicity: cause is unknown but can consits of
confusion, seizures, and altered mental status/coma
• The most common neurologic events of any grade were:
• encephalopathy (11%),
• confusional state (9%),
• delirium (9%),
• tremor (8%),
• agitation (7%),
• somnolence (7%);
• 1 patient had a seizure (grade 3).
• Among grade 3 neurologic episodes that resolved, 50%
resolved within 10 days, and 75% resolved within 18 days
NEJM: 2/1/18
Costs of CAR-T cells• The cost of tisagenlecleucel for pediatric ALL(Novartis) is
$475,000
• Considering the efficacy of this therapy for ALL, the
incremental cost-effectiveness ratio of approximately $46,000
per QALY gained. This falls within the commonly cited
thresholds of $50,000-$150,000 per QALY for all therapies.
• The cost of axicabtagene ciloleucel for Lymphoma (Kite) is
$373,000, not including other costs related to the
administration of CAR T therapy
• Recognizing the less effective therapy and no long term
outcome the preliminary incremental cost-effectiveness ratio of
approximately $136,000 per QALY gained
CAR-T Cells: Conclusions
• CAR-T cells can in approximately 50% of pediatric ALL
patients who are refractory to all prior therapies, be
curative
• CAR-T cells can in approximately 33% of adult DLBCL
patients who are refractory to all prior therapies, be
curative
• Essentially 100% of treated patients will have significant
toxicities including cytokine release syndrome and
neurotoxicity as well as prolonged bone marrow
suppression
• Efforts are ongoing to make these cells more effective,
expand their reach, and less toxic
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