Premal Lulla, M.B.B.S
2018 Funding recipient
Establishing a T cell immunotherapy for MDS
Discovery Research Grant 2018
In normal individuals, blood-forming stem cells within the bone marrow produce new blood cells daily. In some individuals, aging can cause harmful genetic changes that disrupt the normal function of a subset of these stem cells. These damaged stem cells can lead to anemia, infections and bleeding problems in affected patients. These bone marrow diseases are called Myelodysplastic syndromes (MDS) and there is no available cure for the majority of affected patients. In order to reverse the problems associated with MDS, it is essential to eliminate the damaged stem cells. Indeed, bone marrow transplantation, in which all of a patient’s stem cells are replaced with those from another individual, can cure some patients with MDS. However, this procedure is toxic and successful in only 50 to 66% of treated patients.
Specialized blood cells within the immune system, called T cells, are known to eliminate virus-infected and cancerous cells. T cells are able to recognize abnormal proteins produced by cancerous or infected cells as danger signals, which triggers killing. We have identified a panel of abnormal proteins expressed by stem cells from MDS-affected patients and have shown that we can enable T cells to target these abnormal proteins in the laboratory. We hypothesize that treating patients with these MDS-specific T cells will promote normal stem cell function while eradicating the MDS-stem cells and induce long-term remissions.
In this project, we propose to improve the success rate of bone marrow transplantation in patients with MDS by supplementing the transplant with these MDS-targeted T cells. We will make these cancer-killing cells from the patient’s stem cell donor. We believe that given after stem cell transplantation, these cells will enable patients without disease to stay disease free, and also may cure relapse of MDS after stem cell transplantation. We will look closely at blood from treated patients in order to see if the damage caused by these MDS-specific T cells might uncover new MDS-associated proteins to target in the future. If we are able to identify new proteins, we could use them to target disease-causing stem cells even more effectively, enhancing the potency of this therapy.
Many patients with MDS are unable to receive stem cell transplantation due to its toxicity. As stem cell transplant is the only potentially curative therapy available to MDS patients, this large group of ineligible patients needs new and effective treatment options. Thus, in the second part of this study we will test our ability to make our MDS-targeted T cells directly from the patients. Sometimes creating T cell products from cancer patients is difficult due to the treatments they have already received. However, if we are successful, we will have created a very powerful and potentially curative therapy for these patients who have few remaining treatment options.
In summary, at the end of this project we hope to have shown that MDS-specific T cells improve outcomes for patients undergoing bone marrow transplant, and also to lay the foundation for this therapy to be applied to all patients with MDS, not just those undergoing a bone marrow transplant.
Wingchi K. Leung, Aster Workineh, Shivani Mukhi, Ifigeneia Tzannou, Daniel Brenner, Norihiro Watanabe, Ann M. Leen, and Premal Lulla, Evaluation of cyclin A1–specific T cells as a potential treatment for acute myeloid leukemia, Blood Advances, 2019 DOI 10.1182/bloodadvances.2019000715.
Mira Jeong, PhD, Sangbae Kim, PhD, Yumei Li, PhD, Rui Chen, PhD, Premal Lulla, MBBS, Margaret Goodell, PhD, Single Cell Profiling of DNMT3A-Mutant Progenitors Reveals LY86 As a Novel Pre-Leukemia Marker and Potential Therapeutic Target, Blood 2019, DOI 10.1182/blood-2019-123597.
Hussein Hamad, MD, Wingchi K Leung, MD, Spyridoula Vasileiou, PhD, Shivani Mukhi, Quillan Huang, MD, George Carrum, MD, Carlos A. Ramos, MD, Rammurti Kamble, MD, LaQuisa C. Hill, MD, Ann M. Leen, PhD, Premal Lulla, MBBS, T Cell Immunity Toward Viral- and Tumor-Antigens Is Preserved in MDS Patients, Blood 2019, DOI /10.1182/blood-2019-126792.
Premal D. Lulla, Ifigeneia Tzannou, Spyridoula Vasileiou, George Carrum, Carlos A. Ramos, Rammurti Kamble, Tao Wang, Mengfen Wu, Mrinalini Bilgi, Adrian P. Gee, Shivani Mukhi, Betty Chung, Linghua Wang, Ayumi Watanabe, Manik Kuvalekar, Mira Jeong, Yumei Li, Shamika Ketkar, Matthew French-Kim, Bambi Grilley, Malcolm K. Brenner, Helen E. Heslop, Juan F. Vera, Ann M. Leen, The safety and clinical effects of administering a multiantigen-targeted T cell therapy to patients with multiple myeloma, Science Translational Medicine 2020, July 29.