The answer is yes, and no. Advances in just the past five years have proven immunotherapy can stimulate the immune system’s natural capabilities to kill cancer cells, and possibly lead to cures for many patients. So yes, it appears immunotherapy is the best weapon yet against cancer and is poised to deliver a knockout blow to this deadly disease.
But, no, it is doubtful it can achieve such an historic milestone on its own. Many experts believe that combinations of different kinds of immunotherapies, along with traditional chemotherapies and radiation, ultimately will emerge as the most effective strategies.
Although early successes have raised hopes for a widespread cure, it also remains unclear whether even powerful combinations can elicit that outcome for all cancer patients. What seems apparent, however, is that combination therapies will be able to transform cancer, particularly advanced forms of the disease, from a rapid killer into a manageable chronic condition, giving patients many more years and improved quality of life.
WuXi AppTec, a leading global pharmaceutical and biopharmaceutical open access capability and technology platform, assists immunotherapy companies from discovery to manufacturing and beyond. An important element of this support involves offering a communications platform to facilitate the exchange of ideas among the most innovative companies and the creative people behind them.
In this installment of WuXi’s new communications platform on the future of drug discovery and development, leading immunotherapy experts discuss the prospects for conquering the many forms of cancer. They include MPM Managing Director Christiana Bardon, Juno Therapeutics CEO Hans Bishop, Kineta CEO Shawn Iadonato, TCR2 Therapeutics CEO Garry Menzel, and Advaxis Immunotherapies CEO Daniel O’Connor. Their complete interviews also are available on this website.
The idea of cancer immunotherapy has been around for a century. The challenge to its effectiveness has been discovering how to reprogram the immune system’s frustrating lack of interest in dispensing with a deadly anomaly that sits in plain view.
Recent advances in genomics and the discovery of biomarkers related to the disease’s sleight-of-hand in evading detection have escalated expectations that immunotherapy finally is ready to fully enlist the immune system in the war on cancer. The level of excitement over immunotherapy has reached a fever pitch, stoked over the past several years by clinical research data and new drug approvals demonstrating impressive successes. This optimism lies in the confidence that the science of understanding how the immune system works is poised for significantly greater breakthroughs within the next 10 years.
The prospect that a single immunotherapy will dominate in supplanting traditional, standard-of-care chemotherapies and radiation is motivating mega-wagers by public and private investors, seeking to pick the winners among the score of drug developers emerging in this highly competitive field.
Many experts, however, are hedging their bets, forecasting an assault by a combination of immunotherapies, alongside chemotherapy and radiation, to overwhelm a stubborn killer ranked by the World Health Organization as the second leading cause of death globally with an annual economic cost of $1.2 trillion.
Where are we now?
There is no doubt immunotherapy has been broadly embraced as not only “the next big thing” in cancer treatment, but also the best hope yet for a cure among everyone from bench scientists to long-suffering patients. The U.S. National Cancer Institute has described cancer immunotherapy as a transformative technology and a central element of the federal government’s Cancer Moonshot.
The American Society of Clinical Oncology named immunotherapy as the clinical advance of the year in 2016 and 2017. More than 130 biotech and 20 big pharma companies are developing cancer immunotherapy drugs with worldwide sales expected to hit $40 billion in just three years, according to a recent report from Tufts Center for the Study of Drug Development. Immunotherapies are beginning to dominate public and private cancer research funding, drug approvals and, of course, the attention of the public and news media.
The goal of harnessing the immune system to destroy cancer took a major step forward in 2011 with FDA approval of the first checkpoint inhibitor. In the past five years, five checkpoint inhibitors, which are monoclonal antibodies that enable T cells to recognize and attack cancer cells, have been approved for eight types of cancer.
Other forms of immunotherapy include:
- Adoptive cell therapy, in which cancer killing T cells are stimulated to attack tumors;
- Small molecule immune modulators that elicit immunogenic cell death;
- Cancer vaccines, which introduce cancer antigens into the body to generate an immune system response;
- Oncolytic viruses, which infect and kill cancer cells;
- Oncolytic bacteria, which are vectors that deliver cancer antigens to boost the immune systems attack on the disease.
The enthusiasm for the prospect of a cure certainly is not misplaced, and arguably is not overhyped, as most experts agree they have their proof of concept with checkpoint inhibitors. More effective treatments are within sight as scientists are just beginning to understand how the immune-genome works with the revelation of more and more biomarkers related to such a complex and varied disease.
“Checkpoint inhibitors are the most effective immunotherapy approaches to date,” says Christiana Bardon, M.D., managing director of MPM’s Oncology Impact Fund.
Four of the five new immunotherapy drugs inhibit PD-1/PD-L1, which are proteins on T cells that prevent them from attacking other cells, including cancer cells. They have elicited long-term complete responses, essentially cures, in 20% of patients, Bardon notes. That’s a huge improvement over the 5% to 10% of patients whose cancers are destroyed by chemotherapy.”
But it’s not enough, Bardon says. “There are still many patients who don’t respond to these PD-1 inhibitors and we need to understand why. The second thing is that not all cancers respond to checkpoint inhibition.”
These approved checkpoint inhibitors are made and marketed by the traditional big pharma companies and represent the first generation of new immunotherapy approaches. A sampling of other strategies being pursued by the hundreds of smaller biotech companies reveals the broad scope of new therapies under development and underscores the enormous excitement immunotherapies engender.
For example, Juno Therapeutics uses an adoptive cell therapy approach, such as CAR-T cell therapies, which involves engineering T cells to seek and destroy cancer cells.
Juno CEO Hans Bishop says, “We are working on multiple fronts to build on what we have done to date, including focusing on keeping engineered T cells active in the body for a longer period of time; controlling elements of cell expansion in order to improve tolerability; and better understanding what types of cells work best, cell signaling, and how to better equip cells to find cancer.”
Advaxis Immunotherapies alters a live strain of Listeria monocytogenes (Lm) bacteria to stimulate a T cell response against cancer. CEO Daniel J. O’Connor says Advaxis has learned a “great deal about immune tolerance and the multiple mechanisms that protect cancer cells, but we do not know them all. Two elements that protect cancer in the tumor microenvironment that we do know well are regulatory T cells and myeloid-derived suppressor cells that have the ability to shut down a T cell response.”
Kineta’s approach focuses on the innate immune system, which is different from the adaptive immune system that characterizes T cell responses unleashed by the checkpoint inhibitors. CEO Shawn Iadonato says his company is developing small molecule compounds that target RIG-1 like receptors, including RIG-1 and MDA5.
“Targeting these innate immune pathways is a differentiated strategy that can cause immunogenic cell death, elicit neoantigen responses and turn a cold tumor hot,” Iadonato explains. “They are small molecule drugs that can enable rapid drug development and may be dosed orally or systemically.”
TCR2 Therapeutics is developing a different kind of T cell stimulating therapy aimed at solid tumors.
“The T cell receptor (TCR) is a remarkably complex structure that triggers a cascade of biological pathways when bound to a tumor antigen,” explains CEO Garry Menzel. “We seek to harness all of that power by tethering a TCR subunit to a specific antigen binding domain. The key is that this construct is integrated into the TCR so that any signaling on binding the tumor antigen triggers the entire activation cascade rather than only part of it.”
The swiftness of progress in developing immunotherapies is mindboggling and, of course, the reason for all the enthusiasm.
“Only in the last five years,” Bardon notes, “have we figured out that the immune system plays a role. Now there are hundreds and thousands of ways to apply that science and that thinking toward developing new therapies.”
In May 2017, nearly 1,300 cancer immunotherapy clinical studies were listed on the U.S. National Institutes of Health’s ClinicalTrials.gov website. Three years ago, a Nature article estimated that within 10 years, 60 percent of patients with advanced cancer will be treated with immunotherapies.
Where are we headed?
For starters, the immunotherapy field will continue to be dominated by pioneering, risk-taking biotech companies conducting the hard work of innovation with big pharma selecting the best in putting together the most effective combination therapies.
“The truth is that smaller companies are more nimble and more aggressive in bringing innovation to the clinic,” Bardon says.
In the long run, however, Bardon believes the big pharmas and big biotechs with their extensive resources and marketing capabilities will absorb the smaller companies in an aggressive competition to become the lead combination therapy provider. The driver is a potential market for cancer treatments whose upside seems unlimited. For example, Bardon observes, the PD-1 checkpoint inhibitors, the first generation of new immunotherapies, are expected to generate a $20 billion market opportunity.
The investor frenzy over cancer immunotherapy companies is reminiscent of the overly optimistic excitement at the turn of the last century that was heaped on emerging companies attempting to take advantage of the new science of genomics. Many in the patient, investor and research communities were disappointed by overpromised outcomes.
The differences this time around are the dramatic scientific progress in understanding genomics that has occurred in nearly two decades since the full human genome was sequenced and the drug industry’s experience in better managing expectations.
“The clinical data,” says TCR2’s Menzel, “clearly demonstrate that we have entered a new golden age of therapies following mixed success with surgery, radiology and chemotherapy.”
But he notes, “The immune system is very complex and we need a better understanding of how it interacts with tumor cells to enable the very best therapies for patients.”
Juno’s Bishop agrees, saying, “Cancer has a remarkable ability to adapt and evade treatment, and we are relatively early as a field in learning how to harness the potential and adaptability of the immune system to fight this disease.”
For example, while CAR-T therapies, which have generated the most enthusiasm following the success of checkpoint inhibitors, have shown “emerging efficacy” in blood cancers, Bardon says, “We haven’t see any efficacy with CAR-T in solid tumors.”
Another major determinant in the future of immunotherapy involves the realization that combination therapies will be required to break up the mysterious dances between the immune-genome and cancer, choreographed by the differences among cancer types and population groups.
Advaxis’ O’Connor sees two trends emerging.
“First, given the complexities and multiple layers of the immune system and tumor microenvironment, we know the potential of combination therapies holds significant promise,” he explains. “Second, and even more exciting, we see a move away from the one-size-fits-all approach to treating disease as we start to focus more and more on bringing patients personalized therapies tailored to their specific cancers.”
Whether the science can lead to cures for everyone remains far from settled, particularly for patients with advanced, metastatic cancer. However, the experience with the first generation of immunotherapies demonstrates the potential for disarming a killer and significantly improving patients’ quality of life.
As Kineta’s Iadonato observes, “Immunotherapy provides the promise that we can move cancer to being treated as a chronic disease and not simply trying to extend survival.”
Bardon has talked to investors who have seen the powerful efficacy of checkpoint inhibitors and believe a widespread cure for the disease is imminent. “My response,” she says, is “there is still work to be done. I don’t think in my lifetime, we will cure everybody’s cancer, and every type of cancer.”
Bishop also observes, “Our understanding of these products will grow exponentially over the next five years. In five years’ time we expect to begin implementing next-generation strategies that expand the number of patients we can treat, the number of cancers we can target, and the depth and duration of remissions we can begin to expect.”
What challenges do we face?
The scientific challenges of discovering effective new immunotherapies attract most of the attention. But other equally significant challenges involve delivering these therapies to patients. Foremost among them is the design of clinical trials and market pricing. Immunotherapies are targeted to specific biomarkers that vary from cancer to cancer and patient to patient. They are the latest in what was first called personalized medicine and is now referred to as precision medicine.
The challenge for clinical trial designers is that these therapies often reveal significant efficacy in Phase I and II studies involving small numbers of patients. These trials were primarily designed to assess safety and initial evidence of efficacy. The gold standard for efficacy to determine if a medicine can replace standard-of-care is the Phase III trial, which involves many more patients who are randomized to receive either the drug or a placebo.
In addition, subjects in these trials have advanced cancers with no other treatment options. They know what these new therapies can accomplish and they are refusing to participate in placebo-controlled trials. They want to receive the study drug or drugs. This challenge to clinical trial design has generated calls for engaging patients as active partners in clinical trials rather than treating them as passive research subjects. It also has raised serious doubts about the traditional ethical justification for enrolling patients in randomized, placebo-controlled studies.
Government, academic and industry scientists also have pushed for earlier approval of these targeted therapies based on preliminary efficacy findings to avoid expensive Phase III studies. The FDA has implemented expedited approvals for drugs it designates as breakthroughs without requiring randomization studies. Other experts have suggested relying on studies involving larger numbers of patients, all of whom receive the study drug.
A 2016 article in Cancer Treatment Reviews concluded, “In this current era of personalized and targeted medicine, systematic evaluation and development of new design strategies, both for early phase and definitive trials, will continue to be required for proper clinical validation of tailored tests and treatments.”
As for market pricing, industry experts acknowledge it is an issue, which no longer can be ignored.
“We need to build the capabilities to reliably produce these drugs at scale with a distribution and re-imbursement framework that fosters access to broad populations across the globe,” says Juno’s Bishop.
Advaxis’ O’Connor adds, “We are sensitive to the financial burden our cancer patients and families endure and believe our industry needs to take a hard look at where efficiencies can be achieved that will balance the need for industry to recoup product development expenses while also funding the development and advancement of new product candidates to market.”
The projected high cost of immunotherapies also is putting increasing pressure on companies to produce significant, not just incremental, positive outcomes for patients.
“People are willing to pay for a treatment if you can cure their cancer or convert their cancer to a chronic disease. From that perspective you have to swing for the fences to make sure you’re going to have meaningful impact for patients and make sure that the system can find value in your therapy,” Bardon suggests.