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