December 18, 2015 | by Don Diamond Ph.D.
Since the halcyon days of the discovery of monoclonal antibodies 40 years ago, the science and practice of immunotherapy has greatly matured and revolutionized our thinking about the inevitability of a cancer diagnosis. The 40 years of history has been a progressive march to a better understanding of our immune system and how it functions. In parallel, advances in immunotherapy has resulted in approaches which overcome the myriad number of checkpoints and double-edged swords that both control the pathology from unbridled immune activation and its opposite consequence of ignorance in the face of overwhelming danger in the guise of a growing tumor. Indeed, there were dog days not so long ago when the scientific community, the public and anyone who would offer an opinion shared derogatory views of the prospects of using the immune system to successfully fight cancer. Times have changed, and we face a new challenge as a result of the success of the combined forces of academia, small biotech and big pharma that have redirected negative energy and a prior forlorn attitude that tumor immunology has failed. We are now faced with the shocking possibility that the success of the approaches based on the immune system are so great that our health care system may be unable to satisfy the demands of a public wishing to benefit from these discoveries to change their diagnosis from one of sure death to one of extended survival with few side effects that harm their quality of life.
I will outline a series of opportunities and minefields that will require careful discussion to understand where we came from and where we are headed. The explosive impact of immunotherapy on oncology has prompted me to develop a multipart series of opinion pieces that are hopefully imbued with scientific fact that describes the legacy of tumor immunology from the dark days toward where we are now ushering in a revolution in health care. I intend to divide these concepts into three parts with part I describing the current state of the field and some of the more exciting developments that are impacting patient survival. Next, in part II, I will delve into the history of the field, the potholes that delayed progress, and the hopelessness of immunotherapy after an initial burst of enthusiasm four decades ago. Part III of the series will be a frank and objective discussion of the impact of immunotherapy on the ability of our health care system to absorb the tremendous costs that are being levied on patients who seek extended survival with the help of these new therapeutic developments.
Let us begin with a short description of some of the main therapeutic modalities that are shaping a new era in oncology based upon harnessing, activating and redirecting the immune system for the benefit of patients.
Cancer protein antigen vaccines: This is an area of immunotherapy that dates all the way back to the 1970s. Different concepts have been developed over the years, but the original concept was identifying oncogenes and self-antigens from mouse tumors and manufacturing vaccines that would be protective against establishment or progression of the disease in mice. Some of these concepts were translated to human use, but all failed, and the practice has waned in significance in the last five years.
Monoclonal antibodies-cancer antigens: Previous to the effort in cancer vaccines, the Nobel Prize winning strategy of Drs. Georges Kohler and Cesar Milstein was extended to developing antibodies against cancer antigens and using them as therapeutics in cancer patients. Unfortunately, the strategy failed in its original conception, but it laid the groundwork for antibody humanization which is a strategy that was perfected and generalized at City of Hope as a result of the pioneering work of Drs. Arthur Riggs and Shmuel Cabilly.
DNA vaccines: The revolution in biotechnology also touched the vaccine world as pioneering experiments first explored the use of DNA vaccines as cancer therapeutics. To date, the results have been less than stellar, and some of the reasons are similar to those that made the initial concept of a self antigen cancer vaccine unreliable.
Dendritic cell vaccine: This was a very exciting strategy that had its origin in the 1990s and has since fizzled in the last 10 years of development. Many of the strategies have been tested in the clinic, and there is lack of clinical efficacy when various cancer antigen forms are introduced into the dendritic cell. The general approach is to introduce cancer antigens, peptides, DNA and other forms including tumor lysates into autologous dendritic cells and then intravenously administer the preparation into the patient.
Inflammatory mediators: A hot topic in the last 20 years has been to utilize inflammation to incite the immune response to trigger an anti-cancer inflammatory response. This strategy has been tested using various compounds that react with receptors referred to as TLRs (toll like receptors), PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns). Examples include under-methylated DNA motifs referred to as CpG, lipid A formulations, squalene and poly rI:poly rC. The clinical activity of these agents has been moderate and they are now thought of more as helpers or what is known immunologically as adjuvants to assist in cancer vaccine activity.
Approaches that have shown clinical efficacy
Dendritic cells transduced with mini genes expressing altered self-antigens: A more up-to-date approach utilizing dendritic cells has been the recent discovery by investigators at the National Cancer Institute that the most potent anti-cancer immune responses result from recognition of altered or mutant antigens that spontaneously occur in tumors but have the valuable property of being recognized as foreign by our immune system causing the generation of a more potent immune response than unmodified self-antigen. There are a number of examples of tumor regressions in a variety of cancers that have responded well to this therapy. This is the ultimate personalized medicine as each individual has a different mutation in a self-antigen that requires development of a vaccine individually for a successful treatment approach.
T cell receptor-transduced T cells: This approach, which originated some three decades ago, has been refined and has shown clinical efficacy in melanoma, especially when existing lymphoid lineages are depleted using ablative chemotherapy. Reintroduction of autologous T cells that express melanoma-specific T cell receptors has shown dramatic tumor regressions in a number of patients; however, the limitation is that the requirement is rigid that a particular HLA type is recognized by a single T cell receptor, and in general, this technique has been developed for the most abundant HLA type, namely, HLA, A*0201.
CAR-T cells: This approach was made famous by the dramatic clinical remissions in adult chronic lymphocytic leukemia patients treated by Dr. Carl June at the Abramson Cancer Center of the University of Pennsylvania. Additional successes have been with children who developed a disease called ALL that is generally fatal, but there have been dramatic remissions in the majority of children treated with a form of CAR-T cell that targets a B-cell specific antigen known as CD19. These engineered T cells have a chimeric cell surface T cell receptor that is composed of an external domain derived from a high affinity antibody against an antigen such as CD19 and internal signaling domains that interact with cytoplasmic elements that are derived from cell surface T cell receptors that activate the immune system through signal transduction mechanism. This approach causes the destruction of B cells that express the CD19 molecule on their surface to such a degree that patients with a large tumor burden develop a dangerous syndrome called tumor lysis syndrome that can only be controlled using a specific immunosuppressive regimen. Once the tumor is cleared, a value of the therapy is that the CAR-T cells remain as a durable population in many patients guarding against recurrence of the tumor. This approach has been a revolution in the hematopoietic malignancy field, but it remains speculative whether this approach will be effective in solid tumors. Since there are relatively few immunologic therapies that are effective for solid tumors, refinement of the approach to be effective for adenocarcinoma would be a further revolution in the oncology field that would make a large impact on the survival of oncology patients.
Checkpoint inhibitor blockade: One of the most significant advances in immunotherapy and oncotherapeutics has been the advent of monoclonal antibodies that blocks the action of what is known as an immunologic checkpoint. These terms are becoming part of our lexicon, but what do they mean? All T cells have the capacity to proliferate, and if left unchecked, this could lead to a state of uncontrolled growth that resembles a leukemic condition. To prevent that circumstance, T cells employ molecular switches that are activated when a danger signal or pathogen has been cleared, such as at the conclusion of a flu infection. Unfortunately, this same system has been hijacked by tumors and the environment surrounding them to inactivate T cells that are seeking to destroy the tumor by a similar mechanism they might use against the flu pathogen. A series of molecules were identified as long as 35 years ago that seemed to shut down the uncontrolled immune activation. In recent time, antibodies were developed that interfered with this shut down of immunity; hence, the term: checkpoint blockade. What has been observed, first in the laboratory and now more commonly in the clinic, is a strong activation of the immune system leading to resolution of a number of cancers, especially melanoma. There are two checkpoint inhibitor categories in which monoclonal antibody blocking agents have been approved by the Food and Drug Administration (FDA). The first one is known as ipilimumab, developed by Bristol-Meyers Squibb (BMS), but it has strong toxicity associated with it and a minority of melanoma patients have a durable remission. These individuals are generally thought not to be capable of being helped by conventional treatment. This therapeutic can be considered a lifesaving treatment. The second class targets the checkpoint molecule called program death 1, or PD1, and has seen greater response rates in a variety of tumor classes without the intolerable toxicity of ipilimumab. These agents are sold by two companies, Merck (Pembrolizumab) and BMS (Nivolumab), and both have been approved by the FDA for treatment of melanoma and nonsmall cell lung cancer. The response rates are approximately 24 percent in each case in individuals who have incurable disease. The success of these therapies is remarkable and truly ushers a new paradigm in oncology that makes it possible to survive from relapsed cancer when a decade ago, this was surely a death sentence.
I hope this primer of the players and categories in the burgeoning field of immunotherapy has been helpful to you, and you can use it as a scorecard to gauge the relative success of different approaches as academia, startups and big pharma are in a race to maximize the benefit for patients, as well as the bottom line in the case of industry and perhaps more noble outcomes by members of academia.
Look for two additional segments in this series in the next two issues of the Beckman Bulletin that will tackle some of the more complex issues that surround the development of immunotherapy as a revolutionary therapeutic strategy for oncology patients.
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