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Immunotherapy: Paving the Way for Cancer Treatment

Years ago, when the time came to decide, I opted to become a scientist and not a medical doctor. The decision was based on the naïve dream of the boundless challenges that science provided, the desire to break boundaries and solve the mysteries of nature.  Cancer research provided for me the ultimate challenge. My first few years as a post-doc brought me to Dana-Farber Cancer institute where we were embarking on identifying genetic mutations in cancer and signaling pathways that cancers opted for with the possibilities of targeting these from a therapeutic perspective. But simply coming in to work, I faced a bigger challenge: facing little children who came in for their chemotherapy every day. It was a feeling of helplessness- bordering on guilt. Where is the cure? How can I help these innocent little children who are fighting this deadly battle?

At some point, it became obvious to all of us in the cancer community that there was no “magic bullet”. No single cure was in sight. But what also emerged was that early detection offered the patient the most hope. Detecting cancer early was more beneficial as an outcome predictor than surgery, radiation or chemotherapy.  So, many years later, I feel the same excitement in trying to use our expertise in detecting cancer-causing changes in the body and use methods that have only now been developed to follow progression of the disease.

As dreadful a disease as cancer is at an individual level, it also puts an enormous burden on society. According to a GLOBOCAN estimate, in 2012 alone, there were 14.1 million new cancer cases and 8.2 million deaths worldwide. The direct medical costs (total of all health care costs) for cancer in the US in 2011 were $88.7 billion. Moreover, due to a multitude of reasons, the burden has been shifting to less developed countries, which account for about 57% of cases and 65% of cancer deaths worldwide.

Surgery, radiotherapy, and chemotherapy have been the main approaches for treating cancer in previous decades. Great excitement arose with the completion of human genome sequencing in 2003 and the possibility of targeting DNA mutations that were possible “cancer drivers”. Treatment options started to changefrom harsh non-specific chemotherapy to single-agent therapy or “smart bombs” that selected cancer’s ability to survive or propagate based on driver genes. Worldwide spending on cancer drugs has expanded rapidly and is expected to reach over $100 billion this year.

However, in spite of the advent of all the targeted therapies over the last 3 decades, many patients are not being helped at all. As an example, up to a third of patients with breast cancer experience recurrence, which is lethal in the majority of cases.

In this bleak landscape of existing cancer therapies, a new player has emerged in the form of immunotherapy. Immunotherapy has turned out to be an exciting area of discovery research for many different kinds of cancer. However, the concept of immunotherapy is not new and pioneering work by Emil von Behring and Erich Wernicke over 100 years ago showed that animals infected with diphtheria could be cured by injection of sera produced by other animals that had been immunized with an attenuated form of diphtheria. So, for the first time it was demonstrated that immunity could be transferred. Subsequently, pioneering work by William B. Coley, a surgeon in New York known as the father of immunotherapy who injected bacteria into a patient with cancer, demonstrated the possible efficacy of immunotherapy in oncology.

Immunotherapy was cited as the “Breakthrough of the year’’ in 2013 by the prestigious Science magazine and has received wide publicity in national newspapers (e.g., in The New York Times, 2016) and by the news of the remarkable response to immunotherapy by former President Jimmy Carter (who was suffering from a form of skin cancer) to specific antibody treatments. While researchers have known for many years that our immune systems can recognize and attack cancer cells, actual progress made today is the result of new understanding about the complex interaction between the immune system and cancer.


So what Is Immunotherapy?

Immunotherapy is a type of cancer treatment that is designed to stimulate or enhance the body's natural immune responses. Unlike conventional therapy, it does not target the tumor but is directed towards the tumor-responding immune cells of the host.

The immune system (our body’s defense system against infections) is made up of a network of cells, tissues, and organs that recognize and destroy foreign invaders such as bacteria and viruses or abnormal cells in the body. This process is mediated by the ability of the immune system to recognize the difference between “self” and “non-self”. Self means your own body tissues. Non-self means any abnormal cell or foreign invader, such as bacteria, viruses, etc. The immune system is generated in a person in such a way that it will not target anything that it recognizes as a healthy part of self. Herein lies the problem. Cancers arise from our own healthy cells. As part of their malignant growth, cancer cells undergo a number of changes that transform them and they lose resemblance to normal cells. Sometimes our immune system can detect and respond to these differences. But at other times, the cancer cells escape immune cell attack by multiple strategies including by suppression of the immune system.


What are the advantages of immunotherapy?

Immunotherapy agents have four positive attributes:

They are powerful, have exquisite specificity, remain in the patient over time (memory) and they have universal applicability across multiple types of cancer.

So far 15 cancer immunotherapies have been approved for use in various solid and liquid tumors, and several more are in clinical trials awaiting approval by the Food and Drug Administration (FDA).

Immunotherapies can be classified as active (agents that induce a response in non-responsive patients) and passive (agents that stimulate intrinsic immune response in the patients). Active immunotherapies include cancer vaccines (e.g., Sipuleucel-T in prostate cancer), monoclonal antibodies (bind to specific proteins or antigens) (e.g., nivolumab, ipilimumab in melanoma and lung cancer), cytokines (e.g., interleukin-2, interferon-α in RCC, melanoma, NHL). Passive immunotherapies include cell-based therapies that includeactive T cell therapy (e.g., TIL, CAR-T that are not approved by FDA yet), oncolytic viruses (e.g., T-vec in melanoma), bi- and multispecific antibodies (e.g.,Blinatumomab in ALL) and tumor targeting antibodies (e.g., Rituximab in NHL, CLL). In Bangladesh, some of these novel therapeutic modalities are still be unavailable. However, the excitement that the clinical trial data is generating will very quickly reach us, and some of these drugs will become widely available and accepted.

I have joined Praava with the hope that we can help make available the promise of immunotherapy to the cancer patients in Bangladesh. Our goal at Praava will be to provide the tools of molecular diagnostics that are essential in determining patient selection and help the clinician better treat patients with the advanced therapies that are only now becoming available.

While great strides are being made daily with newer targets being identified for selection against which monoclonal antibodies are being generated, variability in patient response pose challenges. However, combinations involving multiple immunotherapies or other cancer therapies such aschemotherapy, radiation, and targeted therapies are providing better outcomes. Thus, the current clinical trial data suggest that combination immunotherapy is the future of cancer treatment.

Now, more than ever, understanding how the immune system works is opening the doors to developing new treatments that are changing the way we think about and treat cancer.