Some Pets



Immunotherapy Background and OverviewDr. John Chretin, DVM, DACVIM, OncologyImmunotherapy has long been regarded as the “holy grail” of cancer treatment. Its purpose is to induce or enhance an immune response and thereby boost the body’s natural defenses to fight cancer. Because of this effect, immunotherapy offers many potential advantages over traditional anti-cancer therapy such as chemotherapy. With traditional anti-cancer therapy, the goal is to directly target and effect cancer cells. Although the response rate may initially be high, the cancer inevitably mutates and acquires the ability to become resistant. With immunotherapy, the treatment is directed at the non-cancerous immune system and not the cancer itself. Hence resistance is unlikely to occur and long lasting, durable responses are possible. Studies using immunotherapeutics, have in recent times demonstrated this in both humans and animals. A critical component of the immune system is the t-lymphocyte (t-cells). They can, directly and indirectly, destroy cells that have the potential to be, or have become, cancerous. Unfortunately, cancer has the ability to camouflage itself, suppress the immune system, and suppress the t-cell’s ability to attack it. The end result is that the function and numbers oft-cells in patients with cancer are significantly decreased compared to healthy individuals. In addition, although t-cells are often found in high numbers in tumors, they are ineffective at destroying them. Cytokines (immune stimulants and growth factors) and especially antibodies are commonly used immunotherapeutics. These can be made in the lab and act like those produced naturally in the body. They target specific proteins on the surface of cancer cells, cells of the immune system and/or cells that support the growth of cancer. When they attach they can activate immune responses allowing immune cells to destroy cancer cells, block the growth of cancer cells, or even serve as vehicles to transport toxins directly to a tumor. For decades many researchers have tried to effectively enhance the natural immune response and specifically the function of t-cells. Until recently, benefits were minimal, and significant side effects were common. A breakthrough occurred in the 1990’s. This was the discovery of CTLA-4, a suppressor on t-cells that when activated functioned as a brake for the immune system. An antibody was developed that blocked the brake and thereby prevented the t-cells from turning off. Clinical trials evaluating this new antibody in humans with advanced, terminal melanoma not only produced a high response rate but also demonstrated that durable long term control could be achieved. In fact this newly created immunotherapeutic was proven to be the first treatment to significantly improve survival time in these patients. The drug was Yervoy (2011, ipilimumab). Clinical trials using this and similar immunotherapies are currently underway for bladder, kidney and numerous other cancers. With its development, studies were finally demonstrating the tremendous potential of the immune system and the ability of immunotherapeutics to lead to significant improvements in the fight against cancer. Because of immunotherapy, patients with advanced, terminal disease who had failed or were refractory to standard of care treatments were found to be experiencing not only responses but long term survival. Another group of antibody based immunotherapeutics being actively researched are the PD-1 inhibitors. Although the ultimate desired effect is the enhancement of the immune system, mainly t-cells, PD-1 inhibitors have broader immune effects compared to the CTLA-4 blockers. The first FDA PD-1 inhibitor approved was pembrolizumab (Keytruda, Merck & Co, 2014). Its approval was quickly followed by nivolumab (Opdivo, Bristol-Myers, 2014). Multiple other PD1 inhibitors are either in clinical trials or being developed (MED 14736, AstraZeneca/MedImmune; MPDL-3280A, Roche/Genentech/Chugai). What has significantly sped up the development and approval of this category of immunotherapeutics is that in the United States, the US Food and Drug Administration has granted a fast track designation for their use in numerous cancers including melanoma, non-small-cell lung cancer, and renal cell carcinoma. It also recently granted breakthrough therapy designation for their use in the treatment of patients with Hodgkin's lymphoma after failure of autologous stem cell transplant.One of the most active areas of immunotherapy research is called adoptive immunotherapy. This process involves directly acquiring autologous t-cells from a cancer patient and either expanding their numbers in laboratories, alone or in conjunction with genetic enhancement, to attack cancer before returning them to the same patient. For reasons that will be more evident in the following section, adoptive immunotherapy is considered by many to be the most exciting and promising anti-cancer therapy available. It results in a reboot of the patient’s own immune system to produce an incredible positive response to typically fatal diseases. In fact response rates of 80-90% are often achieved. There is no doubt that this form of therapy is regarded as the most important form of cancer therapy to arise in the last several decades, and has the potential to cure or provide long term disease control to many forms of cancer when combined with other conventional therapies.In 2014 alone multiple IPO’s for companies exclusively focusing on adoptive immunotherapy occurred. These include Kite Pharmaceuticals, Juno Therapeutics, Immune Design, Affirmed, Bellicum Pharmaceuticals. In fact, Juno Therapeutics was the largest biotech IPO in 2014 and presently has a valuation of $4 billion which is almost unimaginable for a company that's been in existence for just slightly more than a year. Other more established institutions such as Novartis, Celgene, Bluebird, Memorial Sloan-Kettering Cancer Center, the Fred Hutchinson Cancer Research Center and even the National Cancer Institute are active in developing this technology. In animals, several recent studies demonstrated improved survival and response rates with adoptive immunotherapy. Of particular interest was a small pilot study by Dr. Colleen M O’Connor et. al. (2012) evaluating dogs with lymphoma. The study was a translational study performed in an effort to overcome known immune system deficiencies identified in both humans and dogs with cancer. As mentioned before t-cells, (t-lymphocyte) are the key components of the immune system. In particular CD8+ (cytotoxic) t-cells function to protect the body from invaders, including cancer. In patients with cancer the numbers of cytotoxic t- cells are significantly decreased. Also, the ability of these cells to migrate to tumors, replicate and have an anti-tumor effect are significantly suppressed. Adding to these undesirable changes, traditional anti-cancer therapy (radiation, chemotherapy, etc.) leads to the death and depletion of all lymphocytes numbers. This is unfortunate, because when the tumor burden is at its lowest and weakest point following standard therapy, the immune system is likewise compromised. Therefore, the anti-cancer effect of the immune system, which under normal circumstances might be able to eradicate the weakened remaining cancer cells, is not present. When adoptive immunotherapy (t-cell infusion) is performed in patients who have not undergone standard anti-cancer therapy, high responses can be obtained but are not durable. Therefore, the key to long term control of cancer with this form of therapy has been shown to occur when adoptive immunotherapy follows traditional therapy. Dr. O’Connor sought to evaluate the benefit of adoptive immunotherapy in dogs after completion of standard CHOP based chemotherapy for lymphoma. A blood sample was collected at enrollment into the study. From this blood sample lymphocytes were extracted. In a laboratory CD8+, t-cells (CD8+ t-lymphocytes) were specifically grown. At collection, patient CD8+ t-cells had poor immune functioning, growth ability and ability to traffic to tumor cells. Unexpectedly, after being grown in a laboratory, using Dr. O’Connor’s unique techniques, the CD8+ t-cells were found to revert back to normal functioning. The same that would be expected from those cells found in patients without cancer. The benefit to the patient was significantly improved survival and tumor free period (Survival, 167d vs 392d; Tumor free 71d vs 338d). Although this was a small pilot study, proof of principle occurred. The same benefits of adoptive immunotherapy had been demonstrated in dogs as had recently been demonstrated in human pilot studies. One key difference is that little to no toxicity occurred in dogs. This was significantly different to what was observed in humans, especially those that received genetically altered t-cells. In an effort to continue to improve the benefit of this novel therapy, Dr. O’Connor’s techniques and protocol was utilized on dogs undergoing hematopoietic stem cell transplant (bone marrow transplant). It is known that dogs, just like humans who undergo autologous transplants, are not guaranteed a cure. In fact the cure rate is approximately 40% for dogs with lymphoma (approximately 50% in humans). For those who are not destined for a cure, the immediate post-transplant period is when the patient’s tumor burden is at its lowest--much lower than would be achieved with standard chemotherapy alone. In addition, t-cell numbers and hence immune function are also expectedly low and compromised. Hence, the most opportune time for adoptive immunotherapy is in the immediate post-transplant period, during immune system reconstitution. Thus far only a handful of patients have undergone both adoptive immunotherapy and autologous transplant. None have relapsed with their cancer. This is unexpected because with transplantation alone typically one out of every 2 patients will relapse. In the allogeneic setting, it is not irradiation, but an anti-tumor immune response from the donor immune system, that can lead to cure. Unfortunately, even with this more advanced form of hematopoietic stem cell transplantation, cure rates are not 100% whether dog or man. In the event of relapse, however, donor lymphocyte infusions of CD8+ t-cells are recommended. This has led to significant improvements in the overall cure rate for many cancers. Interestingly, allogeneic hematopoietic stem cell transplantation is now beginning to be performed in patients where the transplant itself is not expected to lead to any significant anti-cancer benefit. The reason to pursuing this advanced form of therapy is to prepare a patient to receive allogeneic donor lymphocyte infusions. These infusions, which ultimately lead to an intense immune response, are leading to significant responses and survival times in patients with no other option for therapy. Adoptive immunotherapy has been performed in a handful of dogs undergoing allogenic transplant. All dogs who were relapsing with their malignancy responded. Unexpectedly, multiple types of cancer responded, and even more surprisingly, in some cases, the severity of the tumor burden did not appear to have an influence the response. I cannot overly stress the significance of these findings. The technology that Dr. O’Connor has discovered has been found to have the ability to revert unhealthy immune cells taken from patients with cancer back to normal function. These cells can quickly be grown in high numbers. They are safe to give to dogs with no significant toxicities having occurred. They can be used as adjunctive treatment to standard therapy and in the post hematopoietic stem cell transplant setting. They have the ability to overcome high tumor burdens, where even conventional chemotherapy often fails, and for some where transplant alone did not lead to a cure, did in fact cure. We have seen firsthand what the potential of this form of therapy is, and we are all committed to make it accessible to animals. If one performs an online search for literature and information on immunotherapy or adoptive immunotherapy in particular, it quickly becomes apparent that this technology and approach is new, being rapidly and actively explored, and is considered by many to be the most significant breakthrough discovered for the treatment of cancer. It targets the natural immune system, not the cancer, hence resistance is unlikely to develop; long lasting control and even cure is a real probability. It has the potential to be effective for a variety of cancers, and may one day prove to be the key to the successful management of dogs diagnosed with the most common and terminal cancers such as lymphoma, hemangiosarcoma and malignant melanoma. Companion animals are considered family. Cancer is quickly becoming the leading cause of death for them, as it is for humans. Because more owners seek cancer therapy for their companion animals, it will follow that immunotherapy, as an adjunct to traditional cancer treatment, will become commonplace. ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download