Genetics and Oncology with Martin Broome PhD
Cancer Immunotherapy: Promises and Challenges
By: Martin Broome, Ph.D.
Dawning of a New Age in Cancer Treatment
The history of cancer treatment has seen multiple technological trends over the last 150 years. Each new approach added to the knowledge of the disease and treatment efficacy of those that preceded each advance. Almost appearing medieval by today’s standards, radical surgery to treat malignancy was the method of only resort dating back almost a thousand years. Prior to that, cancer was thought to be untreatable. For a great history of our understanding of cancer and oncology, see Siddhartha Mukherjee’s wonderful book “The Emperor of All Maladies: A Biography of Cancer” ISBN-10: 1439170916.
The word “Tumor” derives from the Latin word “tumere” meaning to swell. Neoplasm, sometimes used interchangeably with tumor, derives from ancient Greek “Neo” meaning new and “Plasma” meaning formation or creation. Though the Ancients had observed and clearly appreciated the abnormal nature of cancerous tissue growth in animals and humans, they did not have the understanding necessary to therapeutically address such a malady.
Centuries later, as medical knowledge advanced and surgery became possible due to advances in aseptic techniques, doctors began to experiment with tumor excision. Fast forward to the end of the nineteenth century, Halsted advanced the idea of radical surgery to treat breast cancer. More is better was his hypothesis. A curious and damning result was soon noted: despite aggressive removal of the tumor and surrounding tissue oftentimes resulting in gross disfigurement of the patient, survival was not a sure or even frequent outcome. Such was the case with each new advance in cancer therapy including chemotherapy, radiation therapy, combination therapy, adjuvant therapy right up to today’s latest molecularly targeted therapies.
What we have come to understand is that cancer is a highly individualized, genetic disease where patient response to any treatment protocol varies widely. Crude, toxic treatments historically had the most success due to the fact that they target the most basic aspects of cancer cells, namely, rapid, uncontrolled cell division, aberrant internal cellular checkpoints and genetic instability. With the advent of modern clinical trials in the 1950’s utilizing powerful statistical methods and carefully designed studies with treatment and control arms it soon became apparent that the very biology of the disease often thwarted effective treatment no matter what modality was employed. In hindsight it seems obvious that many therapies were destined to fail in the face of a disease that “shape-shifts” and is anything but monolithic, right down to the individual cancer cells that make up a tumor.
We now appreciate that upon diagnosis, some neoplasms (cancer) are deadly from the get go. Others are benign (dysplastic) and will never pose a threat, while still others are somewhere in between, so-called indolent carcinoma in situ. What’s more, malignant neoplasia is a moving target that evolves as treatment of any kind is applied. Where does this leave us?
Fortunately, nature teaches us an important lesson here as in many other cases where we are compelled to intervene technologically, despite having limited knowledge. It turns out that we have the most potent cancer therapeutic one could ever imagine within all of us: our immune system! We have come to understand, our very own immune system is highly effective at detecting and eliminating cancer when it “sees” it. We now know this because recent observations show we all have cancer cells that spontaneously develop in us throughout our lives – some estimates indicate up to half a dozen or more per day! Yet, for the most part, we remain cancer free. As we age, however, the incidence of cancer goes up, in part, because our capacity to mount a robust immune response diminishes. Further underscoring the importance of tumor immune surveillance, patients that undergo organ transplants must receive immunosuppressive therapies to prevent organ rejection. In this pharmacologically induced weakened state, these patients are known to harbor a heightened risk of skin and other cancers requiring close monitoring and rapid treatment for the rest of their lives.
How is it then that cancer develops, especially in cases of young, otherwise healthy individuals? This remains a vexing question with no immediate answers except for clear-cut examples of hereditary disease, strong environmental associations (smoking, UV exposure, and carcinogenic chemical exposure) and certain pathogenic causes (HPV, HIV). Sporadic mutations in the sequence of our DNA over the course of our lives mean that cancer, on the whole, is a disease of old age. Even then, we remain cancer free for the most part due to the remarkable, but not limitless, capacities of immune surveillance. For example, most people over the age of 70 will have a mild form of multiple myeloma present in their bone marrow, yet most will not succumb to the disease. Prostate and breast cancers are other good examples: 1 in 3 men and women will experience dysplasia or even carcinoma in situ in those tissues, yet most of these lesions will not progress and only a subset will die from the disease.
We are beginning to understand how to recognize lethal forms of neoplasia (cancer) from benign or indolent forms. The fields of diagnostic biomarkers and advanced imaging have begun to shed a light. Still, we are far from being confident in making a firm diagnosis as to whether someone needs aggressive treatment or not. The default is often overly aggressive treatment which can result in severe consequences owing to the toxic nature of the treatment itself. What’s missing is the appreciation of what keeps indolent disease at bay and what fails when it progresses.
Now it appears we may have the answer: success or failure of immune surveillance. The convergence of molecular and cellular immunology with cancer biology has taught us that cancer cells elicit an immune tolerance not unlike how the developing immune system is “taught” to discriminate self from non-self. Defects in this developmental process can result in an overactive immune response to normal tissue, such as MS, RA, lupus, IBD; or the other extreme leading to an underactive, immunodeficiency such as SCID/”bubble boy” syndrome. Neoplastic cells that overcome a host of built-in cellular defenses such as apoptosis (cell suicide), necrosis and senescence progress to become carcinoma in situ. They may remain there harmless as long as the immune system keeps them in check. However, over time neoplastic cells adapt and evolve under selective immune surveillance pressure, just as we’ve seen occur for other forms of therapy, and a few, or even just one cell, will escape immune surveillance and progress. Can we now apply our recent advances in understanding immune surveillance to identify new drug targets to treat cancer beyond what we’ve tried so far?
Novel Immunotherapy Agents
Taking advantage of insights into tumor biology and what makes tumors different from normal tissues we have begun to advance novel therapies that target tumor specific antigens. First off, it was recognized that tumor specific antigens, that is cancer cell surface molecules unique (or mostly unique) to the outside surface of cancer cell membranes, could be exploited to focus toxic chemotherapy drugs like tiny nanowarheads to the tumor location sparing most normal tissues from so-called collateral damage inflicted by systemic administration of such drugs. Antibody-Drug Conjugates, ADC, have been deployed to treat cancer for the last decade or so, but only recently have had much success due to improvements in linker technology tethering the cytotoxic chemo drug to an antibody directed against tumor antigens. A recent successful example of this is Kadcycla targeting Her2 on breast cancer cells. Taking things a step closer to immunotherapy, Antibody-Dependent Cell-mediated Cytotoxicity, or ADCC, also relies on antibodies directed to tumor-expressed cell surface antigens like ADC does, but instead of being an antigen-targeted warhead they engage the patient’s own immune system to kill the tumor cell. It turns out well-known and widely used cancer drugs like Herceptin (breast cancer) and Rituxan (B-cell lymphoma) were found to work this way only after studies revealed the true mechanism behind their activity after initial mechanistic claims were disproven. In the case of ADCC, immune cells such as Natural Killer (NK) cells are engaged locally with tumor cells and, as their name reflects, elicit cell killing. NK cells along with Complement Factors, serum proteins that assemble to form pores in targeted cells, work together to cause tumor cell death. This opened an important door to designing new agents that directly engage the immune system.
We now find ourselves in a new era of targeted tumor immunotherapy including such exotic agents as BiTEs (Bi-specific T-cell Engager), cancer vaccines, and perhaps most intriguing, “anti-cloaking drugs” such as PD-1 and PD-L1. The latter two target a metabolic signal that tumors use to suppress immune surveillance. Almost every day now we hear encouraging reports about all these new approaches showing promise in treating difficult cancers such as lung, ovarian and pancreatic cancers. Have we reached a new, aesthetically appealing way to treat cancer that recruits our body’s own best weapon guarding against cancer? It’s hard to imagine a better way to do this than with our endogenous immune system harnessed to ferret out every last cancer cell in a patient’s body no matter where they might hide all while sparing normal, healthy tissue!
While all these new, innovative cancer immunotherapy approaches have those of us in the field very excited and optimistic, there remain important questions regarding safety and efficacy. Despite the so-called “low bar” set for the safety of cancer treatment and considering the track record of cytotoxic chemotherapies still in use, one might think any new treatment showing greater efficacy and similar or lesser toxicity would be a welcome addition. Well, there are certain unacceptable side effects that remain off limits, namely heart risk and certain degenerative conditions such as central nervous system damage. Anything that presents an acute risk of death or other substantial harm is not going to make it as a cancer therapy. Unfortunately, immunotherapy in certain forms may present a risk for development of autoimmunity which if manifested in the form of say an MS-like disease would make it unacceptable. Despite rigorous testing in preclinical animal studies, there remains the chance that widespread clinical use of novel immunotherapies could show unacceptable toxicity. We are still at an early stage in understanding the vast complexities of the immune system. Knowing a few key points of intervention are one thing, but comprehensively understanding the elegant, interconnected system that is the immune system developed over a billion years in nature is quite another!
As if safety were not challenging enough, we know from more than half a century employing pharmaceuticals to treat cancer that disease resistance remains a serious issue. Again, we make assumptions about key points of disease intervention that are based on limited knowledge about complex systems we are still only just beginning to understand. Not that we shouldn’t try given the alternative of certain death facing desperate patients who have exhausted all other treatment options. Lessons learned from our collective clinical oncology experience remind us that we should remain humble when it comes to expectations around any novel approach. My own research into cancer therapies targeting key cellular biochemical pathways seemed to hold great promise only a decade ago only to be met with significant limitations manifested in the clinic. Robust responses observed initially soon waned in some patients and the development of resistant disease is not uncommon. We can be proud, however, that we’ve added potent, new weapons to the oncologists’ arsenal. I foresee one of the greatest challenges cancer immunotherapy will face is the over-reliance on individual tumor antigens as reliable markers for disease. For any tumor antigen-based therapy to be effective, the antigen must remain expressed by tumor cells in sufficient amounts to result in a durable response. If that antigen offers an advantage to the survival of the cell, then it will be difficult for the tumor cell to do without it. Unfortunately, biology has a way of utilizing redundancy in critical pathways, survival being one of the most critical. As with targeted biochemical cancer therapies, I expect immunotherapies will also show some spectacular successes, just not in all cases.
The likely outcome from all these heroic efforts will likely be some form of combined therapy utilizing treatments tailored to each patient. If this sounds like you’ve heard this before, you mostly have! The successive clinical history of cancer surgery, chemotherapy, radiation therapy and adjuvant therapy has consistently shown that a combinatorial approach proved to be more effective than any single monotherapy. The difference this time is the degree to which doctors and scientists can now match the most appropriate treatments to the patient with increasing confidence. In this way we should all have great hope for continued improvements in cancer treatment, hopefully at an accelerated rate.
Conclusions and Future Directions
Where does all this leave us now? Prevention is still the best bet in terms of avoiding the scourge of cancer. Failing that, we now have emerging treatments and tools that hold great promise, some of which I hope I have given you a glimpse. It is worth noting in conclusion, however, that there is more to prevention than what your mother or the Surgeon General has told you. Lifestyle choices obviously remain the biggest factor. But it is worth drilling down further into what it means to lead a healthy lifestyle. Beyond what we eat, drink, breathe or are otherwise exposed to, there remains our attitude and state of mental and spiritual well-being. Might some of that also be considered a worthwhile point of intervention for those who suffer from cancer? In fact, increasing study in this area has shown a clear benefit to having a positive outlook for patients suffering from many forms of cancer. How does this occur? We have known for some time that there are biochemical connections made between neurotransmitters produced when patients experience a sense of optimism, well-being and happiness and the vigor of the immune system. Conversely, stress hormones of the neuroendocrine system, namely cortisol, prepare us for fight or flight at the expense of the immune system. Being in a perpetual state of stress, which is common to patients diagnosed with cancer, exacerbates weakness of the immune system. Mainstream oncologists now appreciate this thanks to clinical trials and have incorporated the importance of positive thinking and stress relief in patient treatment. Music and Art Therapy are recognized as legitimate, reimbursable treatments. We can all practice a little of this same approach in our daily lives as a healthy dose of preventative medicine. Make some time to get outside and enjoy nature, reconnect with an old friend, reconnect with your inner spiritual self. Doing so might just rank up there with any other preventative measure you can take!