Research we fund

Although many patients with diffuse large B-cell lymphoma (DLBCL) are cured with standard therapy, others will die from their disease. Survival is significantly worse for African American (AA) patients and those with Epstein- Barr virus (EBV), which is common in patients from Latin America. The reasons behind these poor outcomes are not well understood, in part because most studies of molecular features in lymphomas have not included enough patients from these racial and ethnic groups.

Lymphoma tumors include not just the cancer cells themselves, but also surrounding cells and proteins that help the cancer cells survive. To understand why AA DLBCL patients and those with EBV have worse outcomes, we will look at differences in genes and tumor make-up in a large collection of DLBCL samples with good representation of these patient groups. Our goal is to find the factors most important to target with new treatments to improve survival for AA and EBV+ patients. We will also build innovative models of DLBCL in the lab to (1) discover how tumor make-up and gene changes affect tumors’ response to treatment, and (2) test new therapies designed to benefit AA DLBCL patients and patients with EBV-associated DLBCL.

Overall, our LLS SCOR Program seeks to bridge the knowledge gap in molecular features of DLBCL in underrepresented populations, and fast-track development of novel targeted therapies that can improve outcomes for these vulnerable patients.

In December 2024, LLS made an equity investment in Solu Therapeutics to "Support Preclinical and Clinical Development of STX-0712 in hematological malignancies, primarily in CMML."

Solu Therapeutics is a biotechnology company dedicated to developing next-generation therapeutics to eliminate disease-driving cells in cancer, immunology and other therapeutic areas. The company’s proprietary CyTAC (Cytotoxicity Targeting Chimera) and TicTAC (Therapeutic Index Control Targeting Chimera) platforms enable the development of innovative medicines that combine the target-binding capability of small molecules with the therapeutic power of biologics.

STX-0712 is a CyTAC targeting the GPCR CCR2, which is a selective marker expressed at high levels on pathogenic monocytes. Pathogenic monocytes expressing CCR2 have been shown to be the key drivers in some hematological malignancies. A Phase 1 trial is ongoing to assess the safety and efficacy of STX-0712 in patients with advanced CMML (NCT06950034).

Development of a strong anti-cancer immune response requires coordinated action of the innate and adaptive parts of the immune system, but cancer cells alter their environment to suppress virtually every step in this process, which promotes cancer progression and treatment resistance. One promising strategy could be to target Heat shock protein 70 (HSP70), which plays an important role in both innate and adaptive immunity, and we therefore developed a series of novel antibodies to HSP70, one of which cured mice of multiple myeloma. Based on strong preliminary data, we propose additional studies to better understand how this antibody activates various types of immune cells, how it works against both cancer cells and modifies the immune environment in mouse models, and how it could work even better in combination with other agents against myeloma. Since this antibody is already being developed into a drug for phase I clinical trials, these studies will directly inform its use in the clinic against multiple myeloma, and possibly against other blood-related cancers such as B-cell lymphomas.

Because acute leukemias are very sensitive to radiation, radioisotopes are ideal payloads to arm antibodies against these difficult-to-cure, aggressive blood cancers. Here, we will develop fully human anti-CD123 antibodies carrying the highly potent alpha-emitter astatine-211 (211At) as a new therapy for acute leukemia. CD123 is broadly displayed on acute leukemia cells in most patients and overexpressed on leukemic stem cells but is only found on a small subset of normal blood cells, enabling the use of 211At-CD123 radioimmunotherapy in the transplant and non-transplant setting with limited toxicities to normal tissues.

We have investigated the consequences of p53 loss on stem cell properties, namely clonogenic growth, self-renewal, and drug resistance in multiple myeloma. We have found that both the level of Notch signaling and BCMA impact these properties, and we will explore novel strategies to improve outcomes in p53 mutant multiple myeloma.

Leukemia recurrence remains the most common type of treatment failure after allogeneic hematopoietic cell transplant for children and young adults with high-risk acute myelogenous leukemia (AML), occurring in 40-50% of patients. Novel treatment strategies are needed to attain durable remissions and provide long-term cure. We have developed a novel memory-like (ML) NK cell immunotherapy that has demonstrated potent activity against AML in preclinical and early clinical studies. We propose a new clinical trial combining donor-derived ML NK cells adoptive cellular therapy with modified αβT cell-depleted haploidentical HCT to enhance graft-versus-leukemia and reduce relapse in pediatric and young adult patients with high-risk AML.

T-acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia with limited treatment options after first-line chemotherapy. Our preclinical work in animal models of T-ALL demonstrated the activity of a novel-novel combination treatment strategy, which includes LP-118 (activator of suicide pathways within leukemic cells) and tyrosine kinase inhibitors (inhibiting growth-promoting LCK and ACK1 signaling pathways). Leveraging the mechanistic insights gained from our laboratory work, we propose a phase Ib/II study investigating the feasibility and efficacy of the combined LP-118, ponatinib, and salvage chemotherapy in patients with relapsed T-ALL. This precision medicine approach addresses an unmet need in a fatal disease which lacks effective therapies.

In order to develop a novel immunotherapy approach to treating AML, we propose targeting B7-H3 (CD276), a promising immune checkpoint that has been reported to inhibit NK cell activation. We have generated a novel anti–B7-H3 monoclonal antibody (T-1A5) to block B7-H3 function, showing the best in vitro and in vivo activity against AML cells. We will test the hypothesis that combination strategies such as targeting B7-H3 along with BCL2 inhibition (venetoclax) or IL-15r agonist (NKTR-255) result in synergistic inhibition of AML growth.

RAS/MAPK mutations are the key drivers in MM, which occurs in 50% of newly diagnosed and higher in relapsed MM patients. However, RAS remains undruggable in MM. We found that RAS mutation MM growth is highly dependent on germinal center kinase(GCK). The goal of this project is to develop small molecule inhibitors against GCK with the expected outcome to provide novel treatments for relapsed/refractory and especially multi-drug resistant MM with RAS mutation, as well as other B-cell malignancies.

Patients with CLL that have progressed on BTK inhibitors have high risk disease with few clinical options. Here we propose a novel, selective inhibitor of PKCβ, MS-553, as a strategy for these patients. Our project will evaluate this drug alone and in combination with venetoclax preclinically and will perform correlative studies from an ongoing phase 1/2 trial of this drug alone and in combination with venetoclax.