Making Cancer History - CAR T-Cell Therapy

By Dr. Hue-Tran Hornig-Do.

CAR T-cell Therapy: a Game-Changer in the Fight Against Cancer

Philipp's parents still remember the black day when their son was diagnosed with B-cell acute lymphoblastic leukaemia (ALL); the most common form of childhood cancer. "It was during the summer holidays just after Philipp turned 12. We felt miserable but were trying to be optimistic. After all, acute lymphoblastic leukaemia has one of the highest cure rates for childhood cancers", Philipp´s father recalls.

Shortly after diagnosis, Philipp started chemotherapy and the lymphoma disappeared. But over the next three years, the cancer came back three times. "Another stronger round of chemotherapy couldn't stop the cancer, nor could radiotherapy and then a bone marrow transplant. We didn't know what to do and were completely devastated," Philipp´s mother sums up the last three painful years of treatment, teetering on the edge of hopelessness. At this time point, Philipp´s doctors realised he would qualify for new treatment called CAR T-cell therapy. The treatment was life changing for Philipp. Now, three years after the CAR T-cell infusion Philipp has remained cancer-free and was able to start his studies at university.

What is CAR T-Cell Therapy and How Does it Work?

CAR (for Chimeric Antigen Receptor) T-cells are a form of cell therapy that has achieved exceptional results in some patients.1 The foundation for the development of CAR T-cell therapy had already been laid with the discovery of bone marrow transplantation, where for the first-time live cells were infused into blood cancer patients to attack the cancer. In the case of CAR T-cell therapy, specially engineered white blood cells called T-cells have been used.

As early as the 1900s researchers already knew that T-cells can hunt down and kill abnormal cells including cancer cells. However, for a variety of reasons T-cells don’t always recognise or fully attack cancer cells, potentially allowing tumours to proliferate and spread. To overcome this T-cells need a "signpost" that leads them to the tumours. So, antibodies acting as a kind of “signpost” became a valuable scientific and medical tool. Antibodies are proteins used by the immune system to neutralise pathogens.

The CAR T-cells have a fragment of the antibody that allows them to bind to the tumour. The first chimeric antigen receptor (CAR) was developed in 1987. The DNA coding for this receptor was implanted into T-cells. Once CAR binds to the tumour cell, the CAR T-cells multiply and kill them, thereby helping to clear the tumour from the body.2 Importantly the CAR T-cells remain in the body for years, acting as "sentinels" to summon more CAR-T-cells when needed to destroy scattered tumour cells.

CAR T-Cell Therapy Approvals

In 2011 promising results were reported from both children and adults with ALL. Nearly 90% of the ALL patients showed a complete and rapid response. However, it took another six years before Kymriah was approved by the US Food and Drug Administration (FDA) for the treatment of children and young adults with ALL.3 Since then, six CAR T-cell therapies have received broad approval by the FDA to treat several cancer types (Table 1).4

CAR T-Cell Therapy
Active Substance
Cancer Type
Manufacturer

Kymriah

tisagenlecleucel

Relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL)

Relapsed/refractory large B cell lymphoma

Relapsed/refractory follicular lymphoma

Novartis

Yescarta

axicabtagene ciloleucel

Relapsed/refractory large B cell lymphoma

Gilead

Tecartus

brexucabtagene autoleucel

Relapsed/refractory mantle cell lymphoma

Gilead

Breyanzi

lisocabtagene maraleucel

Relapsed/refractory large B cell lymphoma

Bristol Myers Squibb

Abecma

idecabtagene vicleucel

Relapsed/refractory multiple myeloma

Bristol Myers Squibb

Carvykti

ciltacabtagene autoleucel

Relapsed/refractory multiple myeloma

Janssen Pharmaceutical Companies

Side Effects

Serious side effects like cytokine release syndrome (CRS) and neurotoxicity can occur during therapy.5 Therefore, CAR T-cell therapy must be administered in a medical centre and patients must be closely monitored for several weeks after the CAR T-cell infusion. CRS can cause dangerously high fevers, extreme fatigue, difficulty breathing and very low blood pressure. Neurotoxicity can result in side effects including brain swelling, confusion, seizures, severe headaches and sometimes hallucinations. Experienced centres have learned how to recognise and treat side effects early.

How to Make CAR T-Cells?

Treatment starts with the collecting of a sample of a patient’s T-cells from their blood. The isolated T-cells are sent to a lab where they are genetically modified to express the chimeric antigen receptors on their surface. The modified T-cells are expanded over weeks and shipped back to the hospital. Before CAR T-cell infusion, the patient should have a short course of chemotherapy to clear away their existing white blood cells. When these CAR T-cells are reinjected into the patient, the CAR T-cells identify and attack cancer cells throughout the body.

Research and Future of CAR T-Cell Therapy

To make CAR T-cell therapy more effective, researchers are working on multiple targets leading to novel CAR designs where dual targeting or even triple targeting of proteins on tumour cell surfaces are included.6 In addition to improving efficacy, researchers are seeking to accelerate CAR T-cell manufacturing in order to widen availability. A promising approach is the use of allogeneic or “off-the shelf” CAR T-cells instead of the patient´s own cells.7 Off-the-shelf products that have been genetically modified to minimise the risk of rejection or graft-versus-host reaction can be administered quickly and are also available to those patients who are unable to obtain their own body cells in sufficient quality or quantity.

The Fisher Scientific channel offers a comprehensive portfolio of trusted supplies including culture media and ready-to-use reagents, products for cell isolation, modification and expansion, and resources for purification, filtration, cryopreservation and more. No matter what stage of research, development or manufacturing, we are here to support our customers as a reliable partner. Let's work together to realise hope for the benefit of patients.

References

1. June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S. & Milone, M. C. C. A. R. T cell immunotherapy for human cancer. Science. 359, 1361–1365 (2018).

2. Sadelain, M., Brentjens, R. & Rivière, I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388–398 (2013).

3. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

4. Albinger, N., Hartmann, J. & Ullrich, E. Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany. Gene Ther 28, 513–527 (2021).

5. Sterner, R.C., Sterner, R.M. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 11, 69 (2021).

6. Huang, R., Li, X., He, Y. et al. Recent advances in CAR-T cell engineering. J Hematol Oncol. 13, 86 (2020).

7. Depil, S., Duchateau, P., Grupp, S.A. et al. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 19, 185-199 (2020).

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