Most patients with acute myeloid leukemia (AML) have a poor prognosis, and a “bone marrow” or hematopoietic cell transplant (HCT) is the only chance for a cure. The new immune system that develops in the patient is the active part of the therapy, including natural killer (NK) cells. A major obstacle for HCT in AML patients are the complications that occur due to high doses of chemotherapy. Newer transplant types referred to as “mini” transplants are more tolerable with fewer side effects, but have a high relapse chance. We developed a new method to activate donor NK cells, which result in a long-lived, highly potent memory-like NK cell. These are made from donor immune cells by purifying the NK cells, activating overnight cytokines, and then infusion into the patient. This new NK cell therapy approach has been tested in a phase 1 study at WUSM for patients with AML with promising clinical results and no major side effects. However, without a “matched” immune system, the AML patient’s immune cells reject the donor NK cells after 2-3 weeks, and thus the memory-like NK cells have only a few week “window of opportunity” to eliminate the AML. Here, we combine the “mini” HCT transplant with memory-like NK cell infusion from the same donor to leverage the strengths of each individual approach. We expect that the donor memory-like NK cells will result in a complete remission, allowing time for the new immune system to develop and safely provide a long term cure.
Acute leukemias (acute myeloid leukemia—AML and acute lymphoid leukemia—ALL) are lifethreatening cancers of the blood responsible for 40% of all childhood cancer deaths. For those who survive, life-altering side effects from conventional therapy are common. Despite progressively improved survival, these circumstances are far from ideal. To achieve better outcomes with fewer side effects, we need new treatments that target mechanisms of leukemia cell survival. By focusing on these adaptations we have discovered an “Achilles heel” in leukemia cell survival. We discovered that leukemia cells depend upon a partnership between two proteins, Growth Factor Independence-1 (GFI1) and Lysine Specific Demethylase-1 (LSD1) in order to survive. The GFI1—LSD1 complex promotes leukemia cell survival by blocking genes that cause cell death. Leukemia cells cannot survive without GFI1, even if LSD1 is present, nor can they survive without LSD1 even if GFI1 is present. This suggests that inhibitors of the GFI1—LSD1 axis can trigger leukemia cell death. To this end, we developed a new drug (SP-2577) that selectively inhibits LSD1, overriding pro-survival effects of the GFI1—LSD1 axis and triggering death of AML and ALL cells. Notably, SP-2577 causes death of leukemia cells that are resistant to other drugs currently used to treat leukemia, and thus may provide a treatment for patients with relapsed disease. Our proposal tests the addition of SP-2577 to established treatment regimens for patients with relapsed AML or ALL and validates markers of SP-2577 “on target” activity for future multi-institutional clinical trials.
Acute myeloid leukemia (AML) has the most dismal prognosis of all blood cancers, and >70% of AML patients will succumb to their disease. Therapy is still based on a chemotherapy regimen developed more than three decades ago and what little progress has been made is attributable to improvements in supportive care. Although most patients initially respond to therapy, leukemia stem cells survive in sanctuary sites of the bone marrow and eventually cause relapse and death. Intense research has identified the major DNA mutations in AML, but this knowledge has not led to therapeutic breakthroughs. To overcome this stalemate, our translational medicine research team has taken a function-first approach to identify vulnerabilities in AML cells that are independent of genetic mutations and continue despite protection afforded by the bone marrow. We discovered that cells from most AML patients are highly dependent on SIRT5, an enzyme that regulates energy metabolism, while normal controls are not dependent on SIRT5. As no clinical SIRT5 inhibitors exist, these results prompted us to conduct a search for new SIRT5 inhibitors. We identified a highly promising candidate (HCI-0250) as the starting point for the development of a clinical SIRT5 inhibitor. We will validate SIRT5 as a therapy target in AML using mouse models reflecting key aspects of the clinical disease. In parallel, we will develop a potent and selective SIRT5 inhibitor as a candidate for clinical trials in AML. If successful, our work may lead to a new treatment paradigm applicable to a majority of AML patients.
Funded by the Stuart Scott Memorial Cancer Research Fund
Antibody treatments that block ‘immune checkpoints’ which prevent the immune system from fighting cancer, have resulted in impressive tumor shrinkage and long term survival in many patients with cancer. Results from studies in metastatic triple-negative breast cancer (TNBC) indicate promising activity but not yet the exceptional results seen in tumors known to be highly “immunogenic” or responsive to alterations in the immune system. Strategies to make TNBC “immunogenic” are therefore of great interest as they may result in long term control of TNBC. This is of particular relevance to minority groups such as the African American population, who often present with an aggressive TNBC with limited treatment options available.
Our collaborators at Johns Hopkins have laboratory data, suggesting that combining the histone deacetylase (HDAC) inhibitor entinostat with immune-checkpoint blockade (nivolumab and ipilimumab) led to eradication of breast tumors and long term cures. Research suggests that entinostat may alter the tumor environment by affecting the regulatory immune cells which can prevent immune-checkpoint agents from fighting cancer. This combination may thus be able to convert these traditionally “non-immunogenic” tumors into tumors which can respond to immune therapy.
We are thus conducting a phase I clinical trial of entinostat, nivolumab +/- ipilimumab in advanced solid tumors and patients with TNBC. We anticipate that the collection of blood and tumor specimens during the study will allow us to determine how these drugs are working in patients so we can develop future trials with the hope of significantly improving outcomes for patients with TNBC.
Funded by the Stuart Scott Memorial Cancer Research Fund
Obesity and diabetes are associated with increased risk and worse outcomes for endometrial cancer (EC). African American (AA) women suffer a higher mortality from EC than Caucasian (CAU) women, and this may be in part due to greater rates of both obesity and diabetes among AA versus CAU patients. Metformin is a drug used in the treatment of type 2 diabetes. Our preliminary data finds that metformin has anti-cancer activity, due to its indirect effects within the body (decreased insulin/glucose) and direct effects on EC cells through inhibiting signaling pathways involved in metabolism, including suppression of fatty acid/lipid biosynthesis. Thus, it is logical that metformin may break the link between obesity and EC and emerge as a new targeted agent for the treatment of this cancer.
Our overall goal is to assess the contribution of indirect effects (via decreasing insulin and glucose levels) and direct effects (via inhibition of metabolic pathways and blunting of fatty acid/lipid biosynthesis) of metformin to its overall anti-cancer efficacy in (i) a clinically relevant EC mouse (obese/lean) model and (ii) an ongoing randomized phase 2/3 clinical trial evaluating metformin versus placebo, in combination with standard of care paclitaxel/carboplatin for the treatment of EC. We hypothesize that predictors of metformin response will include both molecular and metabolic biomarkers, specifically obesity, insulin resistance, upregulation of insulin/glucose signaling and heightened fatty acid/lipid biosynthesis, and this response may differ according to race. From this work, we hope to validate metformin as an innovative treatment strategy for obesity-driven EC.
Immune targeted therapies, which stimulate the immune system to attach cancer have revolutionized cancer treatment strategies. These successes have offered new therapeutic avenues for cancer patients, especially for those with lung cancer. Despite the impressive clinical efficacy and duration of responses observed, the fraction of patients with durable responses remains in the order of 20% and there is therefore an unmet need to maximize efficacy of these treatments as well as identify the patients more likely to respond. We propose to use clinical samples from 2 novel clinical trials that combine immune targeted therapy with a different class of medicines, called epigenetic therapy. We have shown that epigenetic therapy may attract immune cells to the cancer site therefore “priming” an anti-tumor immune response. We propose to pinpoint the mechanisms that mediate response and resistance to these therapies by looking at the genetic make-up of cancer cells as well as by studying the tumor microenvironment. We believe our comprehensive, cutting-edge scientific approach linked with ongoing or soon to start clinical trials will result in immediate clinical intervention initiatives and is consistent with our mission to deliver improved treatments to patients with lung cancer.
Funded by the Dick Vitale Gala in Memory of John Saunders
Immunotherapy has given hope to many patients with previously incurable cancers. One of the strongest new immunotherapy techniques is CD19-targeted cell therapy. This is a method of engineering T cells from a patient to attack their own cancer. B-ALL, a type of leukemia, is the most common cancer in kids. In B-ALL, CD19-targeted cell therapy has put over 90% of relapsed patients into remission within a month of receiving these engineered T cells. One problem is that some patients’ cancers learn to hide the CD19 target that these engineered T cells see. The lack of the target allows the cancer to hide from the T cells and come back. This can happen in more than 20% of patients. With this grant, we will explore an alternative target called CD22. CD22 is on more than 90% of B-ALL cells. We will use a combination of CD19-targeted T cells and a drug called inotuzumab that attacks CD22 to prevent the cancer cells from coming back, even if they can hide the CD19 target. We will also develop T cells to target CD22. First, we will move forward with a combination approach using the CD19 cells and the CD22 drug in B-ALL patients. Later, we may use T cells against both CD19 and CD22. Currently, bone marrow transplant is the best option for kids with relapsed disease, but this comes with many risks. As we increase the number of patients remaining in long-term remission with these cell therapies, we can see a future where fewer patients need to undergo the risks of bone marrow transplant.
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