CLL Research Projects
MOON SHOTS PROGRAM
CLL Priority Projects
MD Anderson scientists and physicians have been at the forefront in every major advance against chronic lymphocytic leukemia (CLL) in the last 25 years. Our team developed the current standard-of-care therapy, which might cure up to one-third of CLL patients. Now, the Chronic Lymphocytic Leukemia (CLL) Moon Shot® team is studying more promising treatments for CLL and leading a crucial shift from cytotoxic chemotherapy to well-tolerated oral therapies.
Our ambitious efforts resulted in the approval of ibrutinib for both previously treated and untreated CLL. But this drug is not curative and there are challenges associated with its use, including unpleasant side effects and a prohibitive cost. The CLL Moon Shot team is building on its own successful ibrutinib-related projects to improve the effectiveness of this drug and to identify new therapeutic agents.
At its current dosage, ibrutinib is associated with several side effects and is a cost-prohibitive therapy option for many patients. Our clinical observations and pharmacodynamic evidence suggest that the dose of ibrutinib used to treat CLL patients is unnecessarily high and could be lowered after the first cycle of therapy, while maintaining treatment effectiveness. As a result, both the risk and extent of unpleasant side effects and cost of treatment will likely be reduced, expanding the patient pool that may benefit from this breakthrough drug. We’re currently conducting a trial to compare three different dosages of ibrutinib to determine the level of drug that maintains maximum effectiveness while limiting side effects.
Ibrutinib has many treatment benefits, but it is not curative. Our Moon Shot® team is determined to identify other drugs that work cooperatively with ibrutinib to further improve treatment outcomes. Venetoclax, a targeted therapy that treats CLL in a manner distinct from ibrutinib, shows promising treatment results in relapsed CLL patients who have developed resistance, or did not respond, to ibrutinib. The participation of CLL Moon Shot leader William Weirda, M.D., Ph.D. in the Phase-1 trial demonstrating the benefit of this drug was essential for its FDA approval for treatment of CLL in 2016. Our preclinical studies suggest that combining ibrutinib and venetoclax may further improve treatment outcomes. We’re assessing this combinatorial treatment strategy in the clinic through a Phase II clinical trial examining whether venetoclax and ibrutinib can cooperatively improve CLL patient outcomes.
Unmet therapeutic needs still exist for some CLL patients. By conducting a long-term analysis of 300 patients who’ve received FCR (fludarabine, cyclophosphamide and rituximab) treatment, our Moon Shot team has uncovered characteristics that are associated with long-term, disease-free survival. From this, we’ve identified that patients carrying an unmutated immunoglobulin heavy chain variable (IGHV-UM) gene are at a higher risk for treatment failure and relapse. This information will be used to guide our analysis of the unique molecular characteristics of the CLL cells of these patients, which will benefit future patient-targeted treatment approaches.
For decades, our researchers have lacked laboratory models that recapitulate human CLL, which has impeded the development of a preclinical platform to evaluate targeted therapies. Now, through a collaboration with the TRACTION Moon Shot platform, we’re using a powerful preclinical laboratory model to mimic the disease in our research labs. This effort will more efficiently and effectively guide our evidence-based decision making concerning whether or not a treatment option should move forward to clinical trials.
A hallmark of CLL is improper regulation of the immune system, which may account for increased risk for other cancers in these patients. Common treatment strategies, such as chemotherapy, cause further immune system defects through depletion of immune cells, such as T cells. Allogeneic stem cell transplantation (Allo-SCT) is an alternative treatment strategy that has impressive effects in some CLL patients, but is not a viable option for a majority of patients, particularly the elderly. The curative potential of Allo-SCT is credited to proper restoration of the immune system. With this in mind, our Moon Shot team is developing ways to harness and direct patients’ immune systems to eliminate cancer and restore proper immune function.
Immune cells collected from patients with CLL show that their T cells exhibit high levels of PD1 receptors. When activated, these receptors dampen the anti-tumor activities of the T cell. With this in mind, we’ve initiated two Phase II clinical trials to examine the effectiveness of drugs that block PD1 receptors or the molecule that activates these receptors (PD-L1) in combination with ibrutinib to treat CLL.
Natural killer (NK) cells are the body’s natural response to clearing infection and disease, including cancer. Our Moon Shot team demonstrated that the NK cells of some CLL patients are defective. Now, we’ve identified that cord blood-derived NK cells are able to restore the function of this defective NK cell population. We’ve developed a novel and robust cord blood-derived-NK cell therapy trial to measure the clinical impact of this treatment in CLL patients.
We’re also studying the abnormalities of NK cells found in some CLL patients. A detailed understanding of the defects in NK cell function will help us develop strategies to enhance NK cell function for the treatment of patients with CLL. One such strategy, which expands on our experience with chimeric antigen receptor (CAR) T cells, is the genetic modification of NK cells to recognize a common molecule, CD19, on malignant B cells. Preclinical studies with CD19-specific CAR-NK cells are showing impressive cancer-killing power, and we anticipate bringing this novel therapy to relapsed/refractory CLL patients soon.
The defects in the immune system that result from CLL may also account for increased risk for second cancers. We’ve developed a strategy to reconstitute the immune system of CLL patients using their own T cells. Through our RESTORE trial, patients’ T cells are collected and subsequently enhanced in the laboratory, generating large pools of T cells that are specifically empowered to restore a patient’s immune system. These T cells are then reinfused into the patient to elicit immune reconstitution.
MicroRNAs (miRNAs) are genetic elements that have the potential to affect the irregular gene expression that contributes to the development of all cancer types, including CLL. Our Moon Shot team is using genomic approaches to understand the role of miRNAs in CLL development and progression in an effort to identify biomarkers that predict Richters' transformation and to identify therapeutics targets to overcome ibrutinib resistance.