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CAR-T Cell Therapy and Hematopoietic

Stem Cell Transplantation:

Current Status and Future Directions

RICHARD W. CHILDS M.D.

NIH, BETHESDA MD

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CAR T-Cells: How it Works

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What are CAR-T-Cells and How �Do You Make Them

Apheresis

Stimulation and Transduction

Expansion

Lympho-depletion

Infusion

Image, Courtesy of NIH Medical Arts

Retains the functionality of a T-cell with the antigen recognition properties of antibody
Recognize cell surface antigens independent of MHC, have co-stimulatory signals integrated

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Targeting CD19

CD19 ubiquitously found on B-cells

CD19

B-cell ALL

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CD19 CAR Clinical Updates (Novartis)

Complete Remission Rate = 81%
Event Free Survival Rate

6 months: 73%
12 months: 50%

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Idecabtagene Vicleucel (ide-cel) Chimeric Antigen Receptor (CAR+) T cells For Myeloma: KarMMa Study

CAR-T Cells Targeting BCMA
Pts received a median 6 prior lines of therapy
Almost all tumors expressed BCMA

73% response rate (including 33% CR)
26% of pts became MRD negative
84% CRS (5% >=Gr 3)
PGS 1 year at the highest dose level

Nikhil C. Munshi et al NEJM 2021

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FDA Approvals: CAR T-cells

Kymriah® (tisagenlecleucel): Target CD19

Pediatric B-ALL (up to age 25)
Adults with Large B-Cell lymphoma

Yescarta® (axicabtagene ciloleucel):Target CD19

Adults with Large B-cell lymphoma

Tecartus™ (brexucabtagene autoleucel): Target CD19

Mantle Cell lymphoma

Breyanzi (lisocabtagene maraleucel): Target CD19

Adults with Large B-Cell lymphoma

Idecabtagene vicleucel (Abecma):Targets BCMA

Adults with myeloma refractory or recurrent after 4 lines of therapy

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Will CD19 CAR T-cells be the CURE?

https://emilywhiteheadfoundation.org/

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Current Challenges

Shah NN, Nat Rev Clin Oncol

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Cytokine Release Syndrome

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Stem cell transplantation

Conditioning regimen

Autologous stem cell collection

Patient

Thaw + transplant

Autologous

Freeze

Stem Cells

First-Line Therapy:Multiple Myeloma

Prolongs PFS and survival (Attal et al-NEJM-1996)

Second-Line Therapy:Relapsed Hodgkin’s and NHL

Prolongs survival in NHL (Parma Trial-1995)
Prolongs DFS in HDz (but not survival)

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Stem cell transplantation

Conditioning regimen

Autologous stem cell collection

Patient

Thaw + transplant

Autologous

Allogeneic stem cell collection

Patient

Conditioning regimen

Stem cell donor

transplant

Allogeneic

Tissue or HLA matched

Freeze

Stem Cells

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N=14,270

N=9,720

Slide 2: The estimated annual numbers of transplant recipients in the U.S. were compiled according to the number of first transplants registered with the CIBMTR. Estimates of how closely the numbers reported are representative of actual transplant activity vary according to the type of transplant and number of centers reporting data per year. Prior to 2007, all transplants, except unrelated donor allogeneic transplants facilitated by the NMDP, were reported voluntarily. It was estimated that the CIBMTR captures 90% of all unrelated donor transplants performed in the US, 60-95% of related donor allogeneic transplants and 65 to 85% of autologous transplants. These estimates were extrapolated from other databases that capture transplant center activity, accreditation or hospital discharges. After 2007, the Stem Cell Transplant Outcomes Database (SCTOD) was initiated which changed reporting requirements and data capture to an electronic format. The SCTOD requires that all allogeneic transplants performed in the US be registered with CIBMTR. The numbers of allogeneic transplants from the US in the CIBMTR are representative of the total US transplant activity. Data reporting of autologous transplants remains voluntary and the numbers in the CIBMTR database are estimated to be over 85% in 2019.

The estimated annual number of allogeneic transplants recipients surpasses 8,000 a year in the US in 2013 with 9,498 transplants estimated in 2019, up from 9,509 in 2018. The number of autologous transplants recipients in the US had steadily increased since 2000 with 14,270 transplants in 2019. Autologous transplants still represent over 60% of transplant activity in the US.

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Stem Cells Source

Peripheral Blood

Bone Marrow

Umbilical Cord Blood

G-CSF subcutaneous injection for 5 days. Mononuclear cells collected by apheresis

Direct aspiration under general

Placental blood directly drained into bag

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How Does Myeloablative Allogeneic BMT Cure?

Remission

GVL

Pre-transplant intensive

Therapy

(kill the cancer)

Allograft

(PBSC + Lymphs)

Transplant

-Rescue the bone marrow

-Immunotherapy

T-Cells

1) Conditioning Regimen

2) Graft-vs-Tumor

Leukemia cells

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Allogeneic Hematopoietic Stem Cell Transplantation:

Can Cure Patients With Chemotherapy Refractory

Hematological Malignancies

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May 2006

1 month

After transplant

Nov 2006

7 months post transplant

CSA Discontinued

May 2016

10 yrs post transplant

T-cell Mediated Graft-Vs-Leukemia Effects Can Cure

Chemotherapy Resistant Malignancies

NHLBI Hematology Branch Transplant Protocol 02-H-0250

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Types of Allogeneic Transplants�

Conventional High Dose or Myeloablative Transplant

Conditioning fully eradicates the hosts bone marrow

Reduced Intensity Conditioning (RIC)

Low dose or non-myeloablative transplant
Immunologically eradicates host bone marrow

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Reduced Intensity Conditioning (RIC): Decreases Risk Of TRM But May Increase Risk of Relapse For Some Malignancies

High intensity

TRM

relapse

Low intensity

Conditioning

(RIC)

Possibility of increased risk of relapse (i.e. AML, MDS) with

reduced intensity transplants

TRM= Transplant Related Mortality

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Major Improvements in Transplant Safety Over the Past 2 Decades

Death After Transplant

Day 200 Treatment Mortality

2003-2007-n=1148

2013-2017- n=1131

McDonald G.B. et al Annals Int Med 2020:Ann Intern Med. 2020;172:229-239.

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In the era of precision medicine, why do we still

perform these dangerous allogeneic transplants?

Remains only curative modality for certain diseases associated with short survival with conventional therapy

Relapsed AML
Relapsed ALL
High Risk MDS

Is the only curative modality for many non-malignant debilitating diseases

Sickle cell Anemia
Aplastic Anemia- Relapsed refractory

to IST

Leukemia

Transplant

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Allogeneic Transplant For Hematological Malignancies:�The Earlier the Better !!

CIBMTR Data 2020

Reduced transplant-related mortality and lower relapse with the earlier use of transplants has led to an increasing use of allogeneic transplants upfront for AML in CR-1

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REQUIRMENTS FOR ALLOGENEIC TRANSPLANTATION

An HLA compatible donor to donate stem cells

25% each sibling will be HLA identical
In the U.S., there is approximately a 25% that a patients will have an HLA identical sibling

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Availability of a Stem Cell Sources for Allogeneic Transplantation

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Chances of Finding a Stem Cell Donor

HLA Matched

Sibling

HLA Matched

Unrelated Donor

No HLA Matched

Donor

Potential Candidates

For a Cord Blood Transplant or

A Haploidentical Transplant

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Graft Donor Sources- who to choose?

1) HLA Identical Sibling (SIB)- still best
2) 8/8 Allele Matched Unrelated Donor (MUD)- maybe still 2^nd best
3) alternative donors:

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HLA-Haploidentical related donor (Haplo)

7/8 Allele Matched Unrelated Donor (MMUD)

Cord Blood transplant

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Unrelated Donor Transplants: �Diversity of Adult Donors on the �Be The Match Registry^® 2014

Bone Marrow

Donors Worldwide

52 countries

72 Registries

Probability of finding

a perfect match

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Unrelated Cord Blood Transplantation (UCBT)

Unrelated Cord Blood (UCB) transplants are a transplant option for patients lacking an HLA identical donor:

- Cord blood is a rich source of Hematopoietic progenitor cells- more than human BM

Volume 25 mls

Placenta

Umbilical Cord

Cord Blood Unit

60-80% of patients will have a cord unit in the public registry that could be used for a transplant

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Haploidentical BM Transplants

Transplants that utilize stem cells collected from a relative who

only matches for half of the HLA tissue antigens

Advantages;

Virtually every patient will have a haplo-identical relative to serve as a

stem cell donor

Disadvantages:

- Higher incidence of graft versus host disease

- Obligates use of T-cell depletion

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Post Transplant Cyclophosphamide Following T-cell Replete Haploidentical Transplantation of BM or PBSC

Fuchs E. et al JHU

Chemotherapy to kill cells

That cause graft-vs-host disease

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Ciurea S. et al Blood 2015 126:8:1033-40

Haploidentical Transplant With Post-Transplant Cyclophosphamide has similar outcome to matched unrelated transplants

Survival

Myeloablative Reduced Intensity

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MUD

Cord

Haplo

Sib

Dramatic Increase In Haplo-Identical Transplants

Slide 3: Upon further stratifying the number of allogeneic transplants recipients in the US by donor type, recipients of unrelated donor transplants represent the largest group. The number of unrelated donor (URD) transplants has surpassed the number of allogeneic transplants from related donors after 2006 and the gap between these two types of approaches continues to grow. After 2013, the number of HLA-identical sibling transplants has shown a downward trend in absolute numbers. URD transplants plateaued from 2013-2016 but began rising again after 2016. Transplants performed using alternative donors are increasing. From 2003 to 2011, there was a steady increase in the numbers of transplants using umbilical cord blood (UCB) as a result of several published studies demonstrating its benefit in both children and adults, after which URD UCB transplant activity declined. From 2012 onward, there has been an increase in the numbers of transplants from ‘Other Relatives’, likely due to the use of haploidentical donors with post-transplant cyclophosphamide strategy. After 2014, the numbers of transplants using ‘Other Relatives’ surpassed the total numbers of UCB transplants performed in the US. This trend has continued to rise with these transplants representing 21% of transplants and nearing numbers of HLA-identical sibling transplants which represent 23% of allogeneic transplants in the US in 2019.

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Does the potential benefit of a transplant justify the risk?

(i.e. do I have a disease that chemotherapy can cure or make me live a long time or a disease where chemotherapy is unlikely to cure in contrast to a transplant that has a higher probability of cure

Is my disease controlled sufficiently to where a transplant would help? Timing is everything!!

i.e. Acute leukemias should be in remission before transplant

Do I Have a stem cell donor?

HLA tissue matched sibling
Matched Unrelated donor
Cord blood or haplo-identical donor

What are the chances I could be harmed by a transplant?

Am I Healthy enough to go through the procedure?
Am I young enough?
Have prior treatments put me at increased risk for complications

Questions To Be Answered