White coats to Bowties, Part 1: The silent coup d'état of Cancer Immunotherapy

Aug 23, 2016

Hweixian Penny

Research Fellow

Singapore Immunology Network

The Singapore Immunology Network (SIgN) aims to advance human immunology research and participate in international efforts to combat major health problems. Researchers at SIgN investigate immunity during infections and inflammatory conditions, including cancer, using both mouse models and human tissues.

In his Pulitzer prize-winning book, Mukherjee bestowed on cancer the title “The Emperor of all Maladies”. In 2010 when the book was published, there was little room for disagreement. Today however, with the rise of cancer immunotherapy, a treatment regimen that harnesses our immune system to launch an attack on the tumor, Mukherjee would find pause to reconsider.

The concept that our immune cells can respond to an aberrant growth of self-cells is not new. In the late nineteenth century, Coley, a young surgeon from New York, deliberately infected his cancer patients with bacteria, curing nearly a quarter of them, a statistic astounding even by today’s standards. However, scientists then did not fully understand the mechanisms that underlie infection or tumor regression, and Coley’s work was dismissed and faded into oblivion.

In 1957, Burnet and Thomas put forth the Cancer Immunosurveillance theory, in which they propose that immune cells are able to survey, recognize and eliminate nascently-growing tumor cells in the body. Subsequent decades of research buttressed this hypothesis. It is now understood that the immune response to tumors is as follows. Antigen-presenting cells (APCs) roam and survey the body for ‘foreign’ cells such as tumor cells. The APCs capture and process the tumor material and present it to immature T cells in lymph nodes. This presentation process activates the T cells to proliferate, spew out cytokines and mature.

The maturation process has several downstream effects. Some T cells become effector T cells, which call on another type of immune cell, the B cell, to produce anti-tumor antibodies. Other T cells become killer T cells that traffic back to the tumor and eradicate tumor cells. A subset of T cells retain memory of the tumor antigen so that the body can rapidly respond to a second encounter.

With the surge of cancer immunotherapy these concepts are now widely-accepted — printed over and over again in the highest-quality journals in the world and shouted from the mountaintops. The sad truth is that it was not always this way.

In my first cancer biology class in college, my Russian professor introduced us to the six hallmarks of cancer, as detailed in the seminal treatise by Hanahan and Weinberg in 2000. I had recently decided on an immunology major, and was alarmed that there was no sign of immunology anywhere in the Hanahan and Weinberg paper.

In graduate school, my professors asked the cancer biology class to raise their hands if they believed that there was an immune response to cancer. I raised my hand without hesitation, only to whip my head around the classroom to see that the only other hands raised were my fellow immunologists.

I was beyond flabbergasted. The year was 2006. I held my ground even though I believed staying in the tumor immunology field could mean flying in the face of ridicule, and facing an uphill battle the rest of my career. Thankfully, my misgivings proved unfounded. In a span of a few short years after the turn of the decade, events in the burgeoning cancer immunotherapy pipeline brought about a renaissance.

In 2011, Hanahan and Weinberg published a revision of their initial discourse on the Hallmarks of Cancer. The manuscript now included Immune Evasion. In late 2010, the US Food and Drug Administration (FDA) approved the first therapeutic cancer vaccine for prostate cancer. Within a few years after, three checkpoint inhibitors received approval for advanced melanoma. The data turned heads and silenced critics. Science magazine unabashedly pronounced cancer immunotherapy as “Breakthrough of the Year” in 2013. Tumor immunologists all around the world held hands and celebrated.

Stay tuned for White Coats to Bowties, Part 2 where I will describe current therapeutic approaches in cancer immunotherapy and discuss the change in perspective needed in the design of new cancer treatments.

Hweixian Leong Penny is a research fellow in Wong Siew Cheng's laboratory at the Singapore Immunology Network. She was awarded the NSS-PhD scholarship to study at Brown University for her Bachelor's and then at Stanford University for her graduate degree, where she majored in immunology at both schools. Her primary interest has always been cancer, but she concluded midway through freshman year in college that the best way to battle tumors was by manipulating the body's natural self-defense mechanism — the immune system. By studying immunometabolism in both mouse tumor models and patient samples, she has been on a rescue mission ever since.