Chimeric antigen receptor T-cell therapy (CART- cell therapy) is a novel form of cancer immunotherapy which involves the modification of a patient’s T cells to express a Chimeric antigen receptor that is specific to a particular antigen. CART-cell therapy is a promising treatment for hematological malignancies and has generated substantial results and outcome in the treatment of cancers including leukemia, lymphoma and multiple myeloma. Clinical trials have shown to be effective in the treatment of patients with quite advanced and recurrent cancers even where other available treatments have failed. Despite the remarkable breakthrough of CART-cell therapy in the treatment of hematological malignancies, severe toxicities associated with the administration of CART-cell therapy may compromise its efficacy.

1. CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY IN THE
TREATMENT OF HAEMATOLOGICAL MALIGNANCIES
BY:
IYOYOJIE BLESSING
BMS1702089
DEPARTMENT OF MEDICAL LABORATORY SCIENCE
SCHOOL OF BASIC MEDICAL SCIENCES
UNIVERSITY OF BENIN
BENIN CITY
SUPERVISED BY
MRS .B. ONUYOR-ADAITIRE
FEBRUARY, 2023.

2. OUTLINE
 Introduction
 Laboratory diagnosis
 Chimeric antigen receptor T-cell therapy
 Mechanism of action
 Therapeutic targets in haematological malignancies
 Advantages
 Limitations
 Recent Advancement
 FDA approved CART-cell therapy
 Conclusion
 Selected references

3. INTRODUCTION
 Haematological malignancies are cancers that affect blood
forming tissues, such as the bone marrow or in the cells of the
immune system. They represent 6.5% of all cancers worldwide
and more than 50% of affected patients are over 65 years of age
(Kingsley et al., 2019).
The three main types of hematological malignancies are
leukemia, lymphoma and myeloma, they may originate from
either of the two major blood cell lineages: myeloid and
lymphoid cell lines.

4. DIAGNOSIS
• Complete blood count
• Cytogenetic analysis
• Bone marrow biopsy
• Immunophenotyping

5. CHIMERIC ANTIGEN RECEPTOR –T CELL THERAPY
• Chimeric antigen receptor-T cell therapy is a type of cancer
immunotherapy that uses immune cells called T cells that are
genetically altered in the laboratory to enable them in locating and
destroying cancer cells more effectively.
• This therapy has shown promise in the treatment of some
hematological malignancies, including leukemia, lymphoma and
myeloma and the ability to eradicate very advanced leukemias and
lymphomas and in the management of cancers and to keep them at
bay for a long period of time. (Melenhorst et al., 2022).

6. CAR-T CELL THERAPY
FIRST CLINICALAPPLICATION
• Carl June was the immunologist who led to the development of
CAR-T technology, striving with many difficulties together with
David porter and Stephan Grupp, he administered CAR-T cells to
patient with Chronic lymphocytic leukemia in 2011 (Porter et al.,
2011) and acute lymphocytic leukemia in 2012.
• The real progress was achieved with the first therapy in a child, a 7-
year-old Emily whitehead with relapsed and refractory Acute
lymphocytic leukemia. Her survival helped reenergize a line of
research that was near the future (Rosenbaum, 2017).

7. MECHANISM OF ACTION
• CART-cells can be derived from T cells in a patient’s own
blood (autologously),or the T cells from a healthy donor
(allogeneically).
• For safety, CAR T cells are engineered to be specific to an
antigen that is expressed on a tumor but is not expressed on
healthy cells. (Srivastava et al., 2015).
• The number of the patient’s genetically modified T cells is
“expanded” by growing cells in the laboratory
• When there are enough of them, these CAR T cells are
frozen and sent for reinfusion (Zhao et al., 2018).

8. MECHANISM OF ACTION (continued)
• When they come in contact with their targeted antigen on a
cell's surface, CAR T cells bind to it and become activated, then
proceed to proliferate and become cytotoxic.
• After CAR T cells are infused into a patient, they act as a
"living drug" against cancer cells. (Davila and Sadelain, 2016).
• The therapy has resulted in long-term remissions for some
types of blood cancer. Research has shown that CAR-T cells
can remain in the body and continue to be active for a long
period of time. So, unlike many other blood cancer drugs,
CAR-T therapy is designed to be a one-time treatment.

9. MECHANISM OF ACTION (continued)
Mechanism of action of CART-cell therapy

10. THERAPEUTIC TARGETS
• Currently, CD19 and BCMA (CD269) are the most common targets
in CAR-T cell therapy.
• The CD19 specific CAR-T cells in the B-ALL patients can achieve
an average complete remission rate of 70-94% (Zhang et al., 2020).
• CD22 molecule can possibly be a choice for some relapsed patients
treated with CD19-specific CAR-T cells and two different anti-CD22
agents are currently under clinical investigation (Matsueda et al., 2019)
• Hodgkin’s lymphoma (HL) is an haematological malignancy originating
from B cells and over- expresses CD30 which is a potential therapeutic
target (Yang et al., 2019).

11. THERAPEUTIC TARGETS
therapeutic targets in hematological malignancies (Zhang et al., 2022)

12. ADVANTAGES OF CART-CELL THERAPY
• Rapid recovery
• Ability to treat recurrent cancer
• Potential for long term remission
CAR-T cell is a living biologic manufactured from the patient’s
blood cells. This type of cancer therapy has led to sustained
remission, lesser side effects and better quality of patients’ lives,
making it the preferred treatment plan over the conventional cancer
treatments like chemotherapy, radiotherapy and surgical excision
(Zhang et al., 2020).

13. LIMITATIONS OF CAR-T CELL THERAPY
• Cytokine release storm (CRS) - where excessive release of
cytokines is triggered by CAR T-cell activation, proliferation and
destruction of the cancer cells causing an immune response in the
body (Zhao et al., 2018). Tocilizumab, a monoclonal antibody is
used in the management of CRS.
• Neurotoxicity- CAR T-cells also migrate into the cerebrospinal
fluid, high levels of cytokines in the cerebrum can lead to
aphasia, delirium, seizures. For the management of neurotoxicity,
corticosteroids are favored as they can pass the blood–brain
barrier (Mei et al., 2017).

14. CURRENT ADVANCEMENT IN THE USE OF CART-CELL
THERAPY
Suicide gene switch- Expressing a specific gene into the CAR-T
cells which acts as a safety suicide gene switch to destroy CAR-T
cells when there is development of severe toxicity (Bonifant et al.,
2016).
• Combination therapies - The combination of CAR-T cell
therapy with chemotherapy and radiotherapy to overcome the
restrictions on the use of CAR-T cell therapy, reduce the adverse
effects and increase the efficacy and persistence of CAR-T cells
(Zhao et al., 2019).

15. FDAAPPROVED CART-CELL THERAPIES
• Abecma (idecabtagene vicleucel)
• Breyanzi (lisocabtagene maraleucel)
• Kymriah (tisagenlecleucel)
• Tecartus (brexucabtagene autoleucel)
• Yescarta (axicabtagene ciloleucel)
• Carvykti (ciltacabtagene autoleucel)

16. CONCLUSION
Chimeric antigen receptor T-cells therapy is a promising
therapeutic approach in treating hematological malignancies.
Although limitations still exist, great endeavors have been done to
address them, Research is ongoing to overcome these limitations
and expand the use of CAR T-cell therapy to other types of
hematological malignancies and solid tumors, as well as to
improve the safety and efficacy of CAR T-cell therapy.

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