White coats to Bowties, Part 2: Changing perspectives

Sep 8, 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.

Thank you for returning to White Coats to Bowties. In Part 1, I described the rise of cancer immunotherapy. Here, I will describe current therapeutic approaches in cancer immunotherapy and discuss the change in perspective needed in the design of new cancer treatments.

The current therapeutic approaches of cancer immunotherapy can be broadly categorized into three main areas: non-specific, monoclonal antibodies (mAbs) and cell-based therapies.

Non-specific immunotherapies include cytokines and other immune stimulators. They are often viewed as adjuvants that boost the immune response.

mAbs bind to specific antigens on target cells and facilitate tumor destruction in different ways. They can carry drugs or toxins to tumor cells; tag a tumor cell for killing by immune cells; block or activate signaling pathways on target cells to alter growth and proliferation – this is the category checkpoint inhibitors fall under.

Immune cells naturally utilize ‘checkpoint’ proteins to control and suppress the immune response after a pathogen is cleared, to ensure that the immune response does not persist unnecessarily. T cells have checkpoint proteins like CTLA4 and PD1 that act much like brakes on a vehicle. Engagement of these proteins suppress activation of the T cells. One of the Machiavellian ways that tumors circumvent an immune response against it is by upregulating CTLA4 and/or PD1, effectively staving off the killer attack from T cells. Checkpoint inhibitors get around this by releasing the brakes and unleashing the T cells to launch an unbridled attack against the tumor.

Cell-based therapies consist of harvesting the patient’s own immune cells, stimulating and/or genetically engineering them to better recognize tumor cells ex vivo (outside the body) and re-infusing these immune cells back into the patient. These ex vivo modulations to the patients’ T cells equip them to dispatch the tumor more effectively upon re-infusion. Currently however, Adoptive T Cell Therapy (ACT) is a boutique therapy that awaits scalability.

Despite all the good news, the field is not naïve. Decades of naysayers have taught us to reflect deeply on the full spectrum of clinical, regulatory and manufacturing challenges that this market faces.

Not surprisingly, checkpoint inhibitors work so well in killing tumor cells that they inadvertently attack normal tissue as well and can have serious, though treatable, side effects.

For cancer immunotherapy, several modifications to trial design will help to fine-tune the review criteria. First, the one-dimensional Response Evaluation Criteria In Solid Tumors (RECIST)-defined criteria used for response rates in traditional chemotherapies is not sufficient. In the context of immunotherapy, immune cells often flood the tumor site, resulting in what appears to be an increase in tumor size initially, thus it may take several months before the tumor visibly regresses. Second, the immune response against the tumor often elicits fevers due to its natural ‘pyrogenic’ — or fever inducing — effect. These fevers should not be classified as a negative side effect, as they would in traditional drug development studies. Thirdly, there is a need to define patient responder populations by enforcing a biomarker-driven patient sub-selection strategy. Fourthly, a careful choice of primary endpoints is pivotal. Regulators often desire overall survival but in the context of cancer immunotherapy, it may be prudent for the FDA to emphasize clinical outcomes such as progression-free survival or surrogate endpoints that demonstrate a very strong correlation with extended survival and are true indicators of real medical benefit.

Manufacturing is yet another glaring hurdle in terms of scalability of cell-based therapies. Specialized cell production facilities which can engineer and distribute large quantities of cells that comply with Good Manufacturing Practices (GMP) standards will only exist if companies are convinced of their long-term profitability.

Recently, investigators everywhere have rushed to try all sorts of combinatorial therapies in a haphazard fashion, hoping to hit the jackpot. However, we should take a rationally designed approach to find targeted therapies based on well-understood immune or tumor escape mechanisms. This way, we do not devalue our patients’ lives and the decades of hard science that we have fought so hard to be validated for.

After decades of focusing on cancer genetics, it is now clear that a shift in perspective is required. No longer can the genetic view of cancer dominate how we design new treatments. The ideal treatment regimen would be one that delivers a one-two punch in which the tumor is crippled intrinsically and the immune system marshals an attack extrinsically, retaining immunologic memory in the event of recurrence.

As tumor immunologists of this era, we went from being vilified to vindicated, chaffed to championed, discredited to distinguished. Yet we bear in mind the many challenges we face as we bask in the prevailing exaltation. We remember all the nameless scientists, who never donned suits or bowties for prize ceremonies — just their plain white coats. They, together as a community made the momentous discoveries upon which we built the armory for our current siege against the disease.

In my work here in Singapore, collaborations with clinicians like Toh Han Chong from the Singapore General Hospital and Angela Pang from the National University Hospital, local superheroes who run several concurrent clinical cancer trials, continue to inspire and encourage me with their persistent efforts.

Recently, I sat in a 500-strong audience at a cancer inflammation conference. At the podium was Jim Allison, delivering his closing address. I saw with my own eyes the survival data that had dazzled scientists and oncologists alike and could not help but be blown away myself. I thought of a friend whose mother succumbed to metastatic melanoma years ago, and I struggled to fight back hot tears thinking how she might still be here today if she had received immunotherapy. But then I thought of my son’s grandmother, with her scarlet hair and pale skin under cloudless Kansas skies, and knew that if her melanoma ever came back to haunt her, we would be ready.

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.