Dr. Thakar completed her Pediatric Hematology-Oncology Fellowshit at the Fred Hutchinson Cancer Research Center and University of Washington in Seattle, WA, in 2008. She was recently recruited to the Medical College of Wisconsin for her first faculty position in January 2010. Since her arrival in Milwaukee, she has designed bone marrow transplant clinical trials and translational research projects geared toward overcoming relapse in pediatric patients with high-risk malignancies. Her goal as a Pediatric Oncology and Stem Cell Transplant physician is to continue searching for curable and less-toxic means to treat relapsed patients.
Often the only cure for high-risk hematological malignancies such as leukemia is allogeneic hematopoietic cell transplantation (HCT). However, only 20-80% of patients needing transplants are able to identify suitably-matched donors. For certain groups, especially those coming from backgrounds of high genetic diversity (ie, African-Americans, Asian-Americans), underrepresented ethnicities (ie, Native Americans), or small family units, finding appropriately-matched unrelated donors in the National Marrow Donor Program or within the family is markedly difficult. In order to equalize the opportunity for receiving this life-saving intervention amongst all groups of patients, our institution and others have attempted to optimize the use of human leukocyte antigen (HLA)-haploidentical family members as potential donor sources. Such donors, whose genetic identity is matched by at least 50% to the patient, have emerged as easily accessible, highly motivated, and viable sources of stem cells and have dramatically improved the odds of finding a donor for those patients previously denied transplants. However, due to the immense immunological barriers that must be overcome for this type of mismatched transplant to work, they are often complicated by high rates of relapse, graft-versus-host disease (GVHD), or rejection. These three problems can lead to significant complications, including death. Some groups have been able to successfully overcome these potentially fatal complications using a novel conditioning and immunosuppressive regimen. However, results show that relapse after transplant continues to be a major problem, affecting 51% of patients at 1 year and contributing to a low overall survival of 36% at 2 years1. Unfortunately, patients who relapse after transplantation have limited therapeutic options and often succumb to their diseases2.
In order to provide an anti-tumor boost after transplantation to decrease relapse rates, we are now proposing a Phase I/II study evaluating the addition of an early infusion of donor natural killer (NK) cells to our current treatment plan. Rather than using additional chemotherapy to induce remission, which can be toxic to heavily-treated patients who have already undergone rounds of therapy as well as transplantation, donor NK cells combat cancer using the patient’s new immune system to target malignant cells. NK cells have the advantage over other forms of adoptive immunotherapy such as T cells since NK cells do not need prior sensitization, or exposure, to the tumor proteins prior to destroying them. NK cells have also been shown to promote immune reconstitution, so an additional benefit of receiving NK cells may be to reduce the risk of developing infectious complications during this highly-immunocompromised period after transplant3. Additionally, unlike T cells, NK cells have not been shown to cause GVHD4. GVHD is a life-threatening complication after allogeneic HCT caused by new donor cells attacking the normal host environment with no control. Thus, adding an infusion of donor NK cells, if successful, would solve the relapse problem that we are currently observing in our HLA-haploidentical transplant model with other potential benefits.
The clinical trial is supported by pre-clinical animal studies showing the safety of infusing donor NK cells early after transplant. To further ensure safety, the Food and Drug Administration has granted this cellular product an Investigation New Drug (IND) status and has approved this clinical trial, along with the Investigational Review Boards (IRB) at the two participating institutions. The Phase I portion is a safety trial attempting to identify the dose of NK cells to infuse, while the Phase II portion will continue patient accrual at the winning dose identified from the Phase I trial to confirm efficacy of this intervention. Additionally, we are proposing several immune reconstitution studies, which will help us learn as much as possible about how NK cells work and how we can harness the power of the immune system to control malignancies and develop the next generation of HCT clinical trials to combat cancer. This study is currently open at the Medical College of Wisconsin in Milwaukee, WI and the Fred Hutchinson Cancer Research Center in Seattle, WA.
The collection of donor NK cells requires a substantial amount of support from the Clinical Cellular Therapy Laboratory. The donor must undergo first a marrow harvest for the original transplant, and then undergo an apheresis procedure through a peripheral or central catheter to collect white blood cells. These white blood cells must then be processed using a device known as the Clinimacs®, from which the NK cells will be derived. The cellular processing is performed by highly-trained individuals using sterile techniques and standardized kits. The personnel time and reagents incur substantial financial costs, for which the Hyundai Scholars Grant will cover. Additionally, research tests conducted on this study to understand the influence of NK cells on post-transplant immune reconstitution will be covered by these funds.
