Haider Mahdi, MD

Funded by Lloyd Family Clinical Scholar Fund

Ovarian cancer (OC) is the most lethal gynecologic cancer in the US. Unfortunately, the majority suffer relapse. Patients with recurrent platinum-resistant OC respond poorly to chemotherapy.

Immunotherapy with immune checkpoint inhibition (ICI) has emerged as a promising therapy in several cancers. Unfortunately, only small fraction (10-15%) of patients with OC do benefit from immunotherapy. Therefore, effective strategies are warranted to improve the overall benefit of immunotherapy in OC. Targeting immunosuppressive factors within the tumor immune microenvironment (TME) represents an attractive approach. Our focus in this proposal is on tumor-associated macrophages in OC.

Macrophages with a specific ‘suppressor’ phenotype (M2 subtype) within TME play a significant role in promoting an immunosuppressive environment and in mediating therapy resistance. These cells are the most prominent cells in OC. However, another phonotype (M1 subtype) provides a favorable pro-inflammatory TME and enhances the immune response. Targeting macrophages and switching their phenotype from M2 to M1 is potentially promising approach that has not been investigated thoroughly before. In this study, we propose to target them with two strategies: Targeted inhibition of the transforming growth factor-beta (TGF-beta) receptor and CD47 inhibition. 

Mark Awad, MD, PhD

Funded by Lloyd Family Clinical Scholar Fund

About 5% of non-small cell lung cancers (NSCLCs) have DNA mutations in the anaplasticlymphoma kinase (ALK) gene, and patients with this “ALK-positive” subtype of lung cancer are typically young and have never, or only lightly, smoked. For ALK-positive NSCLC, there are a number of FDA approved oral ALK inhibitor pills, including alectinib, lorlatinib, and brigatinib. While these targeted therapies are initially very effective, the benefit of each of these drugs is usually limited to only a few years because ALK-positive lung cancers almost always develop drug resistance through a variety of complex mechanisms. Although PD-1 inhibitors such as pembrolizumab (Keytruda) have revolutionized the treatment of lung cancer in general, particularly in smoking-associated cancers, most patients with ALK-positive lung cancer do not respond to existing immunotherapies.

We developed an ALK vaccine immunotherapy, composed of small pieces of the ALK protein, which is an effective treatment in animal models of ALK-positive lung cancer. We now plan to launch a first-in-human clinical trial to test this ALK vaccine in patients whose cancer is growing despite treatment with an ALK inhibitor. The vaccine will be tested in combination with an approved ALK inhibitor or with an approved immunotherapy (nivolumab). We will also study immune cells in the blood and in tumor biopsies both before and after vaccination to ensure that this novel therapy is generating a proper anti-ALK immunologic response as we would expect. Our goal is to develop a safe and potent ALK vaccine to improve outcomes for our patients.

Xiuning Le, MD, PhD

Funded by Lloyd Family Clinical Scholar Fund

The Epidermal Growth Factor Receptor (EGFR) gene mutations can be detected in about 15% of patients with lung cancers. In female lung cancer patients who have never smoked cigarettes, as many as 50% of patients have this EGFR mutation. These mutations in the EGFR gene can be different from patient to patient, but all lead to the generation of an active protein that drives cells to survive, proliferate, and become cancerous. Currently, we have efficacious drugs for some of the EGFR mutations, but many other mutations do not have an approved drug. To address this unmet need, I am leading a clinical and translational research program including multiple clinical trials aiming to bring new approvals to treat those atypical EGFR mutations lung cancers. We will collect clinical information and bio-samples (both blood and tissue) to understand why some tumors respond to a certain drug, whereas other tumors not, to characterize the landscape of resistance mechanisms for each group of EGFR mutations. We will test a number of novel drug-drug combinations to overcome resistance and provide more potential options for EGFR mutation lung cancer patients. In this program, we will take a team approach to engage investigators with different expertise, use leading-edge technologies, including computational biochemical approaches and single-cell transcriptomics analysis, and ultimately nominate future therapeutic options for patients.

Conan Kinsey, MD, PhD

Funded by Lloyd Family Clinical Scholar Fund

Pancreatic cancer is an awful disease that kills about 50,000 people a year and is going to be the second most common reason people die of cancer in 2025. We have few treatments for pancreatic cancer that do not work very well and can make patients sick. More treatments for pancreatic cancer that shrink the cancer tumors and do not make patients sick are needed now. Our studies have shown that combining two pills, trametinib and hydroxychloroquine, shrink pancreatic cancer tumors in mice, as well as, in a pancreatic cancer patient. In addition, our previous clinical trial has shown that this combination of pills is easier for patients to take and does not make them sick in a small number of patients. We would like to now see whether the combination of trametinib and hydroxychloroquine pills shrinks pancreatic cancer tumors and leads to a longer life in more pancreatic cancer patients. If our study is successful it might allow for a treatment for pancreatic cancer patients that will make them live longer lives and not cause them to become sick.

Alex Herrera, MD

Funded by Lloyd Family Clinical Scholar Fund

New, non-chemotherapy treatments that use a patient’s own immune system have transformed the treatment of Hodgkin lymphoma (cHL). Typically used in patients with cHL that is resistant to standard treatment, these immune therapies can control the disease for months to years. However, in the long run, most patients will not be cured. Early research suggests that these powerful drugs are safe to use as part of the first or second treatment in patients with cHL and using them earlier could lead to more cures. However, we have not done the research to clarify when is the best time to use immune therapy in cHL and to determine which drugs are best to combine with immune therapy in order to cure more patients. 

My research will answer important questions about the best way to use immune therapy for cHL: (1) How should we use immune therapy as part of the first treatment to cure the most patients and reduce the side effects of our standard treatments? (2) How should we use immune therapy as the second treatment in patients who are not cured by their first treatment?  (3) Can we predict which patients will respond best to immune therapies to help us choose the patients most likely to benefit from these new treatments? And, in cHL patients who are resistant to immune therapy, can we reverse the resistance? 

Daniel Pollyea, MD

Funded by Lloyd Family Clinical Scholar Fund

Myeloid malignancies (myelodysplastic syndrome [MDS] and acute myeloid leukemia [AML]) are very aggressive blood cancers that have limited treatment options. We have learned that these cancers have “stem cell” populations, which allow the disease to propagate, and are the source of relapse when it occurs. One cannot hope to cure these diseases without eradicating the stem cells, but that has historically been very difficult because so little was known about this cell population. We have recently made some breakthrough discoveries related to these stem cells; they have weaknesses that distinguish them from other cell populations in the body, and those weaknesses, which relate to unique ways in which these cells choose to metabolize energy, can be exploited or targeted with particular therapies. Our project seeks to test the theory that specifically targeting metabolic weaknesses in stem cell populations can lead to deep and durable responses for patients with myeloid malignancies. These discoveries will help us to learn how these diseases can ultimately be cured, and will set the stage for the necessary clinical trials that will be designed to do just that. 

Timothy Yap, MD, PhD

Funded by Lloyd Family Clinical Scholar Fund

The term DNA damage response (DDR) inhibitors is used in cancer treatment to refer to a group of drugs, which block important processes that cancers rely on to repair their DNA. While PARP inhibitors (a type of DDR inhibitor) are approved, they do not benefit all patients, and their effects are not long-lasting. Combining PARP (or other DDR inhibitors) with drugs that may boost their effects is a promising approach, which has been shown in laboratory studies (cancer cells or animal testing) to be more effective than each drug given alone. My program of DDR inhibitor combination trials aims to benefit patients with cancers with defects in DDR and other important processes by matching them with suitable DDR inhibitors in combination with carefully selected drugs, therefore personalizing cancer treatment for each patient. Multiple new and promising DDR inhibitor combinations will be tested. Trials not well-tolerated or effective will be stopped early, while trials with promising combinations will be increased in size. We will personalize these treatments for each patient by studying their cancer/blood samples to ensure that the genetic defects of the tumor match the combination treatment, so as to increase the chance of success. If patients stop responding to treatment, they will be allowed to switch to a different DDR inhibitor combination guided by fresh analyses of new cancer/blood samples. This program of trials aims to advance our DDR scientific knowledge, improve outcomes for each patient and guide future trials in order to get better treatments approved. 

Alice Bertaina, MD, PhD

Funded by Lloyd Family Clinical Scholar Fund

Leukemia is a cancer that starts in blood-forming cells found in the bone marrow. It is the most common cancer in children and teenagers, accounting for almost 1 out of 3 cases. Despite recent advances in the treatment of childhood leukemia, a substantial proportion of patients are resistant to conventional treatments. For these children, the probability of cure is very low (<30-50%). The best treatment for leukemia patients, especially those who have not responded to other therapies, is stem cell transplant, but the application of this life-saving treatment has been traditionally limited by a lack of suitable donors. The lack of suitable donors is a particular problem in African American or mixed heritage populations because finding a matched donor is less likely in these populations. We have developed a stem cell transplant strategy that greatly increases the number of patients who can receive transplants. However, this strategy cannot provide the critical anti-leukemic and infection fighting functions required to kill all the leukemic cells and is therefore unable to give patients who receive transplants long term cancer-free outcomesIn this project we will perform three clinical trials designed to test the safety of three innovative cell therapies, which, when given in conjunction with our stem cell transplant strategy, have the potential to fight leukemia. Our ultimate goal is to identify the optimal anti-leukemic cell product that improve cancer-free outcomes for children with leukemia. 

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