CAR- T cell therapy- An exciting new form of cancer treatment

Cancer as we know was once considered an impossible to treat illness. Now, with the help of ongoing research, there is finally a ray of hope in our battle against cancer.

One such field of research is CAR-T cell therapy. CAR-T cell therapy has really changed the landscape of cancer therapy over the years, opening new avenues in the field of immunotherapy.

Firstly before we discuss what CAR-T cell therapy actually is we must understand what a T-cell is-

Image result for t cell cartoon

A T- cell is a white blood cell ( a lymphocyte) which plays the central role in the immune system.
T cells are produced in the thymus(Notice the ‘T’ in Thymus?).

These cells have receptors on their surface (TCRs) which act like a switch. When they come in contact with an antigen or a malignant cell, these ‘switches’ are turned on and the cell is activated which in turn leads to the proliferation and multiplication of that particular T- cell type.

In short, when a T cell is “touch” by a cancerous cell, it just wakes up like that 3 headed guard dog from harry potter.

Mechanism of this Mutation

Mature T cells are of 2 types:

CD4 +ve (helper T cells) and CD8 +ve (cytotoxic T cells).

When T cells detect a certain antigen or a malignant cell they receive two signals-

  1. TCR(T cell receptor) and Antigen binding signal (Acts as the main stimulatory signal)
  1. B7 and CD28 (acts as a costimulatory signal that enhances the above interaction)
Image result for t cell signals
In this diagram the peptide is the foreign antigen or malignant protein recognized by the T cell at the TCR and acts as the main signal and CD80( also called B7) binding with CD28 is the costimulatory signal

Now that the two interactions are in place the T cell secretes a special protein called cytokine which is named ‘Interleukin-2’. This acts upon the T cell, leading to its monoclonal proliferation (proliferation of its same kind).

When CD8 (cytotoxic) T cells are activated they secrete perforin which form pores in the cell membrane of the malignant cell, leading to cell death.
When CD4 T cells are activated they bind to B cells (CD40 ligand on T cells bind with CD40 recptors on B cells). This causes clonal proliferation of the B cells, which in turn produce antibodies against the malignant cells.
CD4 cells in essense instigate other cells called B cells to work against the tumor cells. Hence they’re aptly named “Helper Cells”.

Now that we understood the mechanism of how a T cell works we are now in the position to understand how CAR-T cell therapy works.

CAR-T cell therapy

Essentially cancer cells have ‘stealth’ abilities, in the sense that they can disguise themselves from the soldiers of our immune system and pretend to be one of the normal cells.
So the immune cells fail to recognise these cells as foreign and these cells escape and increase in number.

Image result for camouflaged animals
Cancer cells are like camouflaged predators that can escape immune defense mechanisms

The idea behind CAR- T cell therapy is that we are trying to train the immune cells to recognize malignant cells and kill them.

How are CAR- T cells produced?

CAR stands for chimeric antigen receptor. To design a CAR T cell, we extract a T cell from blood and throw in a CAR gene into it’s gene sequence. This CAR gene cell is then cultured and grown using growth factors, till millions of cells are present in the culture.

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The CAR gene can be modified in a way that it can target any tumor antigen depending on the antigen present in the tumor. There is an immense scope in this therapy as patient specific CAR genes can be developed to produce CAR T cells active against that particular type of tumor.

The CAR receptor

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This receptor consists of an ectodomain and an endodomain.

The ectodomain

The ectodomain is a single chain variable fragment (scFv) of a monoclonal antibody, designed as per the antigen present in the tumor. It binds to tumor antigen. This means that the T cell has now become ‘smart enough’ to bind and recognise the malignant cell which is in disguise.

The endodomain

The binding of the antigen to the ectodomain, results in activation signalling by the endodomain. This signalling causes proliferation of T cells and mounts an immune response against the malignant cell.

CAR T cell has the following benefits

Precise– CAR T cells are extremely precise weapons against the tumor. The binding sites on the receptors bind to that particular tumor antigen and not to other antigens.

Powerful– CAR T cell therapy can get rid of deep seated hidden tumors very effectively.

Memory based– Once CAR T cells are produced they remain in circulation for a prolonged period and can prevent the cancer from coming back again.

How do we administer CAR T cell therapy?

Firstly we screen the patients, after doing preliminary blood investigations, and making sure the patient is fit for therapy. We then grow these cells in culture- this takes about a few weeks time, followed by a quality testing.

3-4 day chemotherapy is then given to the patient which has anti leukemia or anti lymphoma properties, following which these cells are infused. The reason the chemotherapy is given is so that the CAR T cells are better accepted . Patient is then assessed for toxicity.

After the therapy is carried out the CAR T cells continue to multiply in the body and mount an immune response against the tumor. The patient is kept under observation atleast for a week after therapy, in order to tackle side effects if any.

CAR T therapy may have the following side effects.

These are mostly due to an abnormal response-

  1. Cytokine release syndrome- There may be a release of proinflammatory molecules such as interferon- gamma, TNF alpha and interleukin 6 that can cause chills, myalgia, vomiting, decreased apetite and increased heart rate. These symptoms are mild in most patients but can be severe and life threatening.
  1. The systemic cytokines may find its way into the central nervous system and cause diffuse encephelopathy charachterised by drowsiness, delirium, hallucinations, aphasia.
  1. Tumor lysis syndrome maybe seen especially in treatment of blood malignancies, in which extensive destruction of tumor cells can cause spillage of cellular components into the blood stream, giving rise to increased serum potassium, low blood calcium, high uric acid levels and high phosphate levels.
  1. Low WBC and RBC counts maybe seen.

The above mentioned toxicities can be managed with drugs prescribed by the treating physician or they may resolve on their own.

How effective is CAR T cell therapy?

CAR T cell therapy was approved by the US FDA in August 2017. It is indicated in B cell ALL upto 25 years of age.

One of the best response rates was noticed at UPENN, Memorial Sloan and Kettering in which CAR T cell therapy resulted in a 70-90 % complete response in 65 patients over 3 trials mentioned below.

  1. Maude S. L., Frey N., Shaw P. A., et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. The New England Journal of Medicine. 2014;371(16):1507–1517. doi: 10.1056/nejmoa1407222.
  1. Davila M. L., Riviere I., Wang X., et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Science Translational Medicine. 2014;6(224) doi: 10.1126/scitranslmed.3008226.224ra25 
  1. Lee D. W., Kochenderfer J. N., Stetler-Stevenson M., et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. The Lancet. 2015;385(9967):517–528. doi: 10.1016/s0140-6736(14)61403-3.

4 out of 7 patients with DLBCL showed complete response as per the following study.

Kochenderfer J. N., Dudley M. E., Kassim S. H., et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. Journal of Clinical Oncology. 2015;33(6):540–549. doi: 10.1200/JCO.2014.56.2025.

CAR T cells have shown activity against growth factor receptors EGFR, HER2 and VEGF.

The results of this trial seem to be quiet promising but longer trials are needed to confirm the success of this therapy and to decide proper management of side effects. Patients who are refractory to other modes of therapy have responded to CAR T cell therapy.

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