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Tweaking genes to fight cancer: how does it work?

Earlier this month, the United States federal food and drugs regulator approved for the second time in less than seven weeks a new way to fight cancer — a type of gene therapy that turns cells in the patient’s body into a “living drug” that targets and kills cancer cells. How and on which types of cancer does the new technique work? By when and to what extent can gene therapy help patients in India?

What are the two gene therapy products the US Food and Drug Administration approved recently?
On October 18, the USFDA announced its approval of Yescarta (axicabtagene ciloleucel) therapy, a way to fight cancer by an alteration of genes. The treatment, developed by Kite Pharma, a California-based biopharmaceutical company focussed on novel cancer immunotherapy products, is for adult patients with certain types of large B-cell lymphoma (DLBCL), who have not responded to or who have relapsed after at least two other kinds of treatment, USFDA said in its official release.

Before Yescarta, the USFDA had, on August 30, announced its “historic action” in “making the first gene therapy available in the United States”, approving Kymriah (tisagenlecleucel) for certain paediatric and young adult patients (up to 25 years of age) with a form of acute lymphoblastic leukemia (ALL), who had failed to respond to other types of treatments. ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes.

How exactly does gene therapy for cancer work?
Both Yescarta and Kymriah use ‘CAR-T cells’. CAR-T cell therapy works by helping the patient’s own immune system to fight cancer. CAR stands for “chimeric antigen receptor” — engineered receptors that are grafted on to the patient’s ‘T cells’. T cells are a type of lymphocytes (a kind of white blood cells) that destroy infected or cancerous cells. After their re-engineering in the lab, T cells are called CAR-T cells. Once they are re-introduced into the patient’s bloodstream, the army of CAR-T cells multiplies, and goes after the cancer cells. Each dose of Kymriah or Yescarta is a customised treatment that is created using the individual patient’s own T cells.

Large B-cell lymphoma (DLBCL), which Yescarta fights, is a type of non-Hodgkin lymphoma (NHL). NHL is one of two types of lymphoma. Lymphoma is a cancer of the lymphatic system, which is the network of tissues and organs that transports lymph, the fluid that contains infection-fighting WBCs. The other kind of lymphoma is called Hodgkin lymphoma (HL), or Hodgkin disease. Both HL and NHL are cancers that start in WBCs called lymphocytes, but the specific kind of lymphocyte involved is different in each type of lymphoma.

NHL is the more common type of lymphoma. According to the worldwide Globocan 2012 report, the estimated incidence of NHL in India was 23,801 (age-standardised rate (world) of 2.2), just under three times the incidence of HL. The age-standardised mortality rate (world) was 1.5. Neither is among the five most frequently occurring types of cancer in India.

In the US, approximately 72,000 new cases of NHL are diagnosed each year, of which the occurrence of DLBCL is approximately one in three.

What do experts say about the new breakthroughs?
A USFDA release quoted its Commissioner Scott Gottlieb as saying the approval to Yescarta “marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases”. “In just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer,” he said.

A multicentre clinical trial on more than 100 people found that 72% of patients treated with a single infusion of Yescarta responded to therapy, and 51% had “no detectable cancer remaining”, according to Kite Pharma. “The results have been remarkable,” Frederick L Locke, co-lead investigator of the trial, named ZUMA-1, was quoted as saying in a statement. The trial was carried out at the Moffitt Cancer Center in Tampa, Florida, where Locke is Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy.

Are there any known risks in the treatment?
Yes. USFDA has said that Yescarta has the potential to cause severe side effects, and directed that patients must be informed of them before the therapy. Among potential complications are cytokine release syndrome (CRS), a response to the activation and proliferation of CAR-T cells, which leads to high fever and neurological problems. “Both CRS and neurologic toxicities can be fatal or life-threatening. Other side effects include serious infections, low blood cell counts and a weakened immune system. Side effects from treatment with Yescarta usually appear within the first one to two weeks, but some side effects may occur later,” USFDA has said.

During the trials, 13% of patients experienced grade 3 or higher CRS, 31% experienced neurologic toxicities, and two died from side-effects. Both Yescarta and Kymriah are being allowed only gradually, and will be available with a trained set of oncology professionals.

Is this good news for India?
Dr Shripad D Banavali, Head of the Department of Medical Oncology at Tata Memorial Hospital, Mumbai, said the new therapy is efficacious, and good news for everyone across the world. “Anything new is costly,” Dr Banavali said. “But it is new hope for India as well. Here in India, CAR-T cells are being developed by Tata Memorial Hospital and IIT Bombay, along with the US National Cancer Institute,” he said.

Yescarta is meant to be infused into a vein, and must be manufactured individually for each patient. The cost will be $ 373,000 (over Rs 2.4 crore), The New York Times reported.

“We are working to develop CAR-T cells. Not only for NHL, the same treatment is being explored for other types of cancer as well, because its potential is vast,” Dr Banavali said. “Thousands can benefit from this treatment. It is required very much.”

Dr Ashok Vaid, chairman, Medical and Haemato Oncology, Cancer Institute, at Medanta in Gurgaon, said, 40,000 lymphomas are diagnosed ever year in India. “The country should focus on developing its own CAR-T cells, which is the only way forward; otherwise only those who have the reach and resources will be able to avail of these expensive therapies by going aboard,” Dr Vaid said.

Currently, experts say, patients with large B-cell lymphoma in second or later lines of therapy have poor outcomes since nearly half of them either do not respond, or relapse shortly after bone marrow transplants.

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