Promoting Innate Immunity Against Acute Myeloid Leukemia via Inhibition of MICA/B Shedding

Acute myeloid leukemia (AML) is a blood cancer that kills thousands of American patients (military and civilians) every year. Members of the military are at a higher risk of dying of AML because are frequently exposed to carcinogens and radiation. The human body has a mechanism of immunity against cancers, and this immunity is key for the therapeutic efficacy of hematopoietic stem cell transplantation (HSCT). However, HSCT may cause a lethal immune-related toxicity called graft-versus-host disease, and matched donors are not always available. Our goal is to develop a treatment that harnesses the antileukemia immunity without causing lethal toxicity, thus serving as an alternative to transplantation.

In previous studies, we developed a drug that promotes immunity against AML cells while sparing healthy cells. We show intriguing preliminary data that our drug inhibits leukemia in a mouse AML model. We also show clinically relevant data that another drug, which is Food and Drug Administration-approved for cutaneous T-cell lymphoma and is being tested in clinical trials with AML patients, is mechanistically associated with our own drug. For this reason, we also propose to test the hypothesis that combining these two drugs enhances therapeutic efficacy in AML patient-derived xenografts. If successful, this research will help to develop a clinically relevant means to stimulate antileukemia immunity. We envision that our research will help to support a transition to clinical phase by generating an evidence-based rationale about the therapeutic activity of our new drug.

The Principal Investigator (PI): The PI's overall goal is to become an independent investigator focused on cancer immunotherapy. He has a strong track record of research article publications and has made seminal contributions to the field. He recently started his own laboratory in a renowned school of medicine, but has not received extramural funding from federal grants yet. This award will provide a financial support to achieve his goal because it will enable ordering of supplies needed to complete the research project and pay partially the PI's salary. Specifically, this award will: (1) support the construction and publication of a new research article in which the PI will be the senior author, (2) enable generation of preliminary data for future grant applications that will secure the continuity of this project, and (3) help to advance this drug development project towards a clinical phase.

Applicability of the Research: Treatments that harness the immunity are called 'immunotherapies.' They have revolutionized cancer care, and the field's pioneers (Drs. James Allison and Tasuku Honjo) received the Nobel Prize in Physiology or Medicine in 2018. Although certain immunotherapies (e.g., checkpoint blockade) have generated impressive cure rates in patients with, for example, metastatic cancers, they have generated discouraging results in clinical trials with AML patients. The probable reason for this failure lies in the fact that AML employs distinct mechanisms to suppress immunity that are not targeted by the current immunotherapies.

Despite the fact that checkpoint blockade has been disappointing in AML, it is repetitively tested in new but substantially redundant trials with more AML patients. We propose to diversify the immunotherapeutic armamentarium. To do so, as briefly explained above, we are studying a drug that targets an essential mechanism of immune escape extremely relevant to a sub-set of AML patients. Of note, we propose to broaden the applicability of our drug by combining it with the one that is currently used for lymphoma. Furthermore, our drug distinguishes AML cells from healthy cells, even though they have similar origins, thus suggesting that our approach may be well tolerated. However, we acknowledge that the potential toxicity of our drug is unknown, and this question will be addressed in other studies that are out of the scope of this present proposal.

The overall goal of this current project is to generate essential knowledge about the mechanisms of action and therapeutic effectiveness of our new drug. This type of study is commonly called 'translational' or 'preclinical' research and is absolutely essential for the development of new and better treatments. If successful, upon completion of this research we will have built a pre-clinical package that will help to make into clinical phases. Therefore, our research will, in the long term, help to increase the options of immunotherapies available for clinical studies with AML patients.

How This Research Benefits Members of the Military and Their Families: AML is more dangerous to military members compared to civilians, and is frequently incurable. There are no immunotherapies for AML yet. This research will help to fill a gap in the treatment for AML and has potential to cause a broad impact on this patient population, including members of the military, their families, and the general public. Altogether, our proposed research is clinically relevant and has a transformative potential in the standard-of-care for AML by helping to develop a novel immunotherapy.