COVER STORY

Three cheers

Personalised medicine, immunotherapy and gene editing—the future of cancer treatment

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A 54-year-old teacher came to see me for a second opinion with metastatic breast cancer in 2014. Her cancer had already spread to her brain, liver and lungs. Because of the extensive lesions in her lungs, she couldn’t breathe and was on oxygen. Her pain was unbearable.

Her breast cancer was triple negative, which is an aggressive subtype of breast cancer (15 per cent). This type of breast cancer doesn’t express oestrogen receptor/progesterone receptor and Her-2 neu protein. Because this type of breast cancer is more common in patients with BRCA mutation (germline mutation), we tested her blood for that gene. Her testing showed that she carries BRCA 1 gene, which is seen in about 5 per cent of all breast cancers. Then we did next-generation sequencing (somatic mutation) of her tumour. Her tumour had multiple mutations, including BRCA mutation.

Based upon all the information, we selected a treatment plan for her. That regimen included a PARP inhibitor (Olaparib), which targets the germline BRCA mutation. She was part of our clinical research trials using a targeted therapy. She is more than three years post completion of treatment and cancer free. She is working full-time, playing tennis and riding bike to raise money for cancer research.

As per the World Health Organization and the American Cancer Society, one in eight deaths worldwide is due to cancer, and it is rapidly becoming a global pandemic. There were 14.1 million new cancer cases and 8.2 million cancer deaths in 2012. But the good news is that major advances are happening in the field of cancer research and therapy. The three areas that will change the future of medicine, especially cancer treatment are: personalised or genomic medicine, immunotherapy and gene editing.

Personalised and genomic medicine

Cancer is a broad diagnosis of many different unique diseases, often named after its organ of origin. Even within each diagnosis, for example, breast cancer can be divided into three to five different subtypes. As you can see from the patient’s story above, by understanding the biology and using germline mutations or next generation sequencing, we can potentially identify dominant pathways of cell proliferation. That will give us potential targets and novel treatment options. Most of the premier cancer centres in the US use next generation sequencing to select patients for genomically driven clinical trials. We have a genomic tumour board, comprising clinicians, genomic experts, pathologists and clinical research experts. We review each patient’s story and next-generation sequencing reports and finalise the treatment plan. National Cancer Institute's MATCH trial is one of the largest genomically driven trials.

The challenge and opportunity with this approach is that there are many mutations for which we don’t have the right drugs to use. We need more clinical trials using genomic data. This will change the future of cancer treatment.

Immunotherapy

Scientists have been trying to harness our immune system to attack cancer cells since the 1940s. Over the past five to ten years, immunotherapy has emerged as the major cancer treatment approach. It has revolutionised treatments of some of the refractory cancers such as melanoma, lymphoma, lung cancers and bladder cancer.

There are four different types of immunotherapy approaches: monoclonal antibodies, CAR T-cell therapies, immune checkpoint inhibitors and cancer vaccines.

Monoclonal antibodies: The immune system can make a large number of antibodies to attack foreign substances, such as cancer. An antibody is a protein that attaches to a specific protein called an antigen. Scientists have designed many antibodies that specifically target a certain antigen, such as one found on cancer cells. They can then make many copies of that antibody in the lab. These are known as monoclonal antibodies (mAbs). Monoclonal antibodies such as trastuzumab (for Her-2 positive breast cancer), and rituximab (CD20 lymphoma) have completely changed the treatment of this diagnosis. There are antibody drug conjugates, which are one of the highly targeted drugs, combined with monoclonal antibodies.

CAR T-cell therapy: Our immune system keeps track of all the substances in our body. If the immune system doesn’t recognise any new substances, it will raise an alarm and attack them. CAR T-cell (Chimeric Antigen Receptor T-cell) therapy is a promising new way to get immune cells called T-cells to fight cancer by changing them in the lab so they can find and destroy cancer cells. CAR T-cell therapies are otherwise categorised as a type of gene or cell therapy, or an adoptive cell transfer therapy. There are two CAR T-cell therapies approved—for recurrent acute lymphoblastic leukemia and refractory non Hodgkin’s lymphoma.

Immune checkpoint inhibitors (PD-1 and PDL-1 inhibitors): It is important for our immune system to recognise what is normal and what is foreign. By doing this the immune system can attack the foreign or cancer cells and leave the normal cells alone. But immune cells have breaks or checkpoints to control when an immune cell will or will not attack or mount an immune response. Cancer cells effectively use these checkpoints to avoid being attacked by the immune system. But drugs that target these checkpoints such as PD-1 and PDL-1 blockers hold a lot of promise as cancer treatments.

Vaccines to help treat cancer: Cancer vaccines help the immune system to attack cancer cells in the body. Cancer vaccines may be made up of cancer cells, parts of cells or pure antigens. Sometimes a patient’s own immune cells are removed and exposed to these substances in the lab to create the vaccine. Once the vaccine is ready, it is injected into the body to increase the immune response against cancer cells. One of my colleagues at Cleveland Clinic, Dr Vince Tuohy, has developed a vaccine to prevent certain types of breast cancer in preclinical models. Now we are planning to take that preclinical concept to see if it can work in patients.

Gene editing

Gene editing is a technology that gives scientists the ability to change an organism's DNA. This will allow scientists to add, delete or modify genetic material. Several approaches to genome editing are used. One of the most commonly used ones is CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats) and CRISPR-associated protein 9. This is an exciting technology—it is faster, cheaper, more accurate, and more efficient than other existing genome editing methods.

If the ongoing research continues to show the same promise, it can potentially prevent and treat many illnesses, including blood disorders such as sickle cell disease, hemophilia and cancer.

Cancer treatment has changed dramatically in the past 16 years I have been doing cancer treatment and clinical research. It is amazing that some of the most non-curable cancers have transformed into chronic disease or curable disease. But we have a long way to go. Countries like India have to create a safe and ethical environment for clinical trials. Otherwise, our patients will not be able to access novel therapies in a timely manner.

Abraham is director of breast oncology program and professor of medicine, Cleveland Clinic, Cleveland, US.

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