Cancer is an uncontrolled growth and multiplication of cells in a given organ (for example, the lung or stomach), which are damaged due to inborn (genetic) or external triggers (such as smoking or high doses of radiation). While normal cells are programmed to multiply and grow to a certain size and stay so, cancer cells, whose DNA is mutated due to such damage, go on a rampant growth leading to tumours, weakening the body and ultimately even death.
Treating and winning over cancer has been a great challenge, and the oncologist-writer Siddartha Mukherjee has rightly named cancer as “The Emperor of all Maladies.”
There have been a variety of approaches to win over this emperor. Surgical removal of the tumour has been one option, but it does not guarantee total removal (even a few leftover cells might grow again), nor its recurrence if the original cause is not addressed. Radiation therapy using high power gamma rays has also been tried, again with limited success.
Several anti-cancer drugs, such as cis-platin or carboplatin, 5-fluorouracil, doxyrubicin have been used. Many doctors have tried combining drugs along with shining the tumour using radiation such as gamma-rays for short periods of time. But the trouble is that they need to be used for sustained periods.
Immunological approach
It is here that immunological approach has been tried for a variety of cancers. This uses the in-built defense mechanism in the body. The white blood cells play a main role here. The B-Cells therein recognize the shape of the surface protrusion (call it the biometric ID) on the invading cell (be it a microbe or a cancer cell), synthesises proteins called immunoglobulins which fit into the surface of the invading cells and remove them. Importantly, this shape of the intruder’s surface is “remembered” so that when a fresh attack by the same invader occurs, B cells are prepared. This too is the basis of childhood vaccines.
The surface geographic “tag” is termed the antigen and the proteins made by B-cells are called antibodies. Cancer cells also have biometric IDs, and these are termed neo-antigens. Anti-cancer vaccines are based on the principle of antibodies made against such neo-antigens. Antibodies such as bevacizumab and rituximab are some of the most popular drugs used against cancers. (The ‘mab’ at the end of these names refers to monoclonal antibody).
A recent approach in the field is to for the oncologist to isolate a piece of cancer tissue from the patient, and collaborate with a group of molecular bio-analysts to identify the neo-antigen on the cancer cells. Next, the oncologist asks an immunologist collaborator to prepare the specific antibody molecule, which can be injected to the patient so as to stop recurrence of the tumour. This is thus a therapeutic vaccine (not a preventive vaccine such as the one against hepatitis or mumps). Some such cancer vaccines are already in the market, for example, HER-2 against breast cancer, Revenge against cancer and T-VEC against melanoma.
The Nobelists
It is here that this year’s Nobelists have taken a different approach. They concentrated not on the B-lymphocytes but their partners, the T-cells. T cells release chemicals that push the invading cells to commit suicide (what is called apoptosis). Each T-cell has claw-like receptors on its surface that locks into antigens- foreign or abnormal. But the T-cell needs to be activated by certain proteins (called T-cell accelerators) before it triggers such a response. Additionally, there are also other proteins that help check the T-cell from going on a rampage. These proteins are called ‘brakes’ or “check point proteins”.
Dr James Allison of the MD Anderson Cancer Centre at the University of Texas, Houston, TX, USA, has been working since the early 1990s on one such “brake” or “checkpoint “protein called CTLA-4, which down-regulates the immune response of T-cells. He wondered whether one could find a mechanism (or a protein) which can release this brake on CTLA-4. By 1994-95, his group produced a molecule called “anti-CTLA4”, which, when injected on mice with cancer, unlocked the anti-tumour activity and cured the mouse of cancer. As the Nobel committee writes: “despite little interest from the pharmaceutical industry, Allison continued his intense efforts to develop this strategy into a therapy for humans. Promising results from emerged, and in 2010, an important clinical study showed striking effects in patients with advanced melanomas, a type of skin cancer. In several patients, signs of remaining cancer disappeared. Such remarkable results have never been seen before in this patient group”.
This brings us to the work of the Nobel-sharer Tasuku Honjo, currently at Kyoto University, Japan. He discovered, even before Allison, in 1992, that a protein called PD-1 is expressed on the surface of T-cells. His continuing work on it showed that it too is a checkpoint protein; if it were released, T-cells can exhibit anti-tumour activity. Towards this, he developed the antibody Anti-PD1, which when introduced for the treatment of patients with different types of cancer, the results were dramatic.
The trick in both instances, Allison’s or Honjo’s, is to find molecules that will release the brake or the checkpoint, and let the anti-cancer activity occur. As one would expect, research in to checkpoint inhibitors is booming. As a columnist writes: “more than 1100 PD-1 related trials are under way; immunotherapy is now the hottest field in oncology and one that is likely, over the next five to ten years, to transform the way that many cancers are treated”.
With the advances made by the Allison’s and Honjo’s groups, it does appear that the Emperor’s reign may indeed come to an end sooner than later.
dbala@lvpei.org
