HCL2025: Expanding Research in Hairy Cell Leukemia
The Hairy Cell Leukemia Foundation (HCLF) and The Leukemia & Lymphoma Society (LLS) have joined forces to launch HCL2025, a 5-year, $10 million research initiative. HCL2025 supports studies of innovative treatments and novel management strategies in HCL. Through HCL2025, we will fund about $2,000,000 per year in HCL research, with a portion of the funds dedicated to the registry.
To launch HCL2025, we issued an open RFP. A review committee composed of leading HCL experts reviewed and made funding recommendations. We have now awarded multi-year grants to eight investigators at some of the world’s best cancer research and treatment centers.
Developing Novel Therapeutic Approaches for Classical and Variant HCL
Dr. Omar Abdel-Wahab and Dr. Jae Park, Sloan Kettering Institute for Cancer Research, New York, NY
Project Term: October 1, 2021 to September 30, 2025
Project Summary: In this proposal, we have combined clinical and research expertise in HCL across Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, the University of Pennsylvania, and Yale University to develop newer targeted therapeutics for every stage and subtype of hairy cell leukemia. Capitalizing on this combined expertise, our proposal stands to significantly advance treatment strategies for hairy cell leukemia through the following aims: to test BRAF inhibition for initial treatment of classical hairy cell leukemia, test new oral inhibitors of the MAP kinase signaling pathway known as ERK inhibitors in both classical and variant hairy cell leukemia, evaluate totally new treatments that degrade BRAF, and develop T-cell immunotherapies for the first time in hairy cell leukemia.
Lay Abstract: Hairy cell leukemia (HCL) is a blood cancer driven by activation of the MAP kinase signaling pathway. Although chemotherapy results in high initial response rates, HCL is incurable and 40% of patients require repeated courses of chemotherapy which leads to immunosuppression and risk of additional cancers. To this end, it was recently discovered that nearly 100% of patients with classical HCL (HCLc) have a BRAF gene mutation and respond to the oral BRAF inhibitor drug vemurafenib. Despite these advances, some HCL patients develop resistance to vemurafenib and the success rate using vemurafenib for the initial treatment of HCL is unknown. In addition, a rarer form of HCL known as variant HCL (HCLv) lacks the BRAF mutation and HCLv patients are therefore not eligible to receive BRAF inhibitor therapy.
Targeting Oncoembryonic Antigens ROR1 and ROR2 For Therapy Of Patients With Hairy Cell Leukemia
Dr. Thomas Kipps, University of California, San Diego
Project Term: July 1, 2022 - June 30, 2025
Project Summary: We will study the function of ROR1 and ROR2 on HCL cells that we have collected from 120 patients, examining whether they influence expression of genes that can promote the growth/survival of HCL cells. We have made antibodies that are highly specific for ROR1 or ROR2 that react with HCL cells, but not normal blood cells or tissues. We will determine if these antibodies can be used as naked antibodies, antibody-drug conjugates, or in chimeric receptors on T cells to specifically kill HCL cells.
Lay Abstract: Despite improvements in therapy for patients with hairy cell leukemia (HCL), there still is no cure for this disease and some patients, particularly those with the variant form (HCLv), fail to achieve durable responses to current therapies. Needed are new targets for therapy. We discovered ROR1 and ROR2 are on the surface of HCL cells. ROR1 and ROR2 are proteins that play a vital role in the generation of organs in the embryo, but are no longer needed or found on cells of healthy adults. However, we found ROR1 is on cancer cells, which use this protein to promote movement, survival, proliferation, and self-renewal. We generated the first highly-specific monoclonal antibody (mAb) against ROR1 (UC-961, cirmtuzumab) that can block the function of ROR1; this mAb has promising clinical activity when used to treat patients with B-cell malignancies, either as a so-called ‘naked’ antibody, or as an antibody-drug conjugate (or ADC), which is comprised of UC-961 linked to a toxin that can be delivered specifically to the cancer cell. We also developed a new mAb specific for ROR2 that, unlike previous anti-ROR2 antibodies, binds only to ROR2, and not ROR1 or other proteins, normal blood cells, or post-partem tissues, but nonetheless binds strongly to HCL cells. ROR1 and ROR2 thus represent cancer-specific targets that we can use to direct the killing of HCL cells, including the HCL stem cells that potentially are responsible for the return of the disease after initial therapy. We propose to examine HCL cells for these proteins and study whether and how they affect the expression of genes that promote the survival, proliferation, and self-renewal of HCL cells. For this study we have collected and stored viable leukemia cells from 120 HCL patients and have developed methods to study how these proteins influence the expression of genes that promote the continued survival or self-renewal of HCL cells, even in patients who apparently have responded well to initial therapy. We will study whether these highly specific mAbs can block the function of ROR1 and/or ROR2 in HCL and examine whether they are effective in killing HCL cells either as naked antibodies, ADCs, or in chimeric receptors that can arm T cells to specifically kill HCL cells.
Precision Targeting of HCL using Chimeric Antigen Receptor T-cells
Dr. Marco Ruella, Perelman School of Medicine at the University of Pennsylvania
Project Term: July 1, 2022 - June 30, 2025
Project Summary: Though effective treatments in hairy cell leukemia and variant (HCLv) exist, they are associated with profound immunosuppression; thus, more targeted, non-toxic therapies are warranted. In order to specifically target leukemic cells while sparing most normal B cells, we will develop a novel chimeric antigen receptor T cell immunotherapy against the IGHV-4-34 B-cell receptor that is found in a significant subset of HCL and associates with poor prognosis.
Lay Abstract: For the Hairy Cell Leukemia Foundation-Leukemia & Lymphoma Society HCL2025 initiative, we have assembled a group of co-Principal Investigators from different but complementary disciplines (Dr. Ruella, UPenn and Dr. Ghia, San Raffaele Hospital) and collaborators (Drs. Schuster, Stamatopoulos and Tiacci) to tackle the issue of precision treatment of Hairy Cell Leukemia (HCL). CAR-T immunotherapy is a novel type of cancer therapy that includes the engineering of patient’s own immune cells to recognize and fight cancer. CART immunotherapy has been very successful in certain cancers, e.g. cancers of B cells, a particular subset of normal immune cells, responsible for the production of antibodies. However, CART therapy can also lead to profound immunosuppression due to killing not only neoplastic but also normal B cells, rendering the patients prone to infections. This is of special concern in conditions characterized by inherent immunosuppression, including hairy cell leukemia, the focus of the proposed research. Therefore, we aim to develop a CART immunotherapy that does not kill all normal B cells and that is more selective for the hairy cell leukemia cells. To this goal we studied a hairy cell leukemia antigen called IGHV4-34 that is expressed in 40% of the most aggressive hairy cell leukemia called “variant” and also in a subset of classic hairy cell leukemia. We plan to develop a novel CART immunotherapy against IGHV4-34 that will kill hairy cell leukemia cells while sparing normal B cells. We will test this new immunotherapy in the laboratory and using murine models. We will also study the effect of this CART against hairy cell leukemia cells obtained directly from patients and against normal B cells obtained from healthy donors and patients. We will compare the efficacy and safety of this novel CART (IGHV4-34) to the currently FDA-approved anti-CD19 CART that leads to profound immunosuppression in patients. This study will significantly impact the field of cancer immunotherapies by developing a novel targeted anti-hairy cell leukemia immunotherapy. This proposal is highly relevant to the goals of the HCL2025 initiative and will significantly impact our understanding of hairy cell leukemia and hairy cell leukemia variant pathogenesis and treatment. We expect that thanks to the results of this study, we will be able to start a phase I clinical trial of anti-IGHV4-34 CAR T cells for IGHV4-34+ hairy cell leukemia.
Exploiting Metabolic Dependencies, Tumor Plasticity and their Consequences for Drug Response of Hairy Cell Leukemia
Dr. Marc Seifert, Institute of Cell Biology (Tumor Research) at the Medical school Essen, Germany
Project Term: October 1, 2021 to September 30, 2024
Project Summary: We have long standing experience in the field of HCL research. The aim of this research proposal is to characterize HCL on single cell level across multiple layers to uncover interactions of HCL with its microenvironment, which supports HCL cell survival. We will further explore metabolic and functional dependencies of primary HCL cells, and we hypothesize that their attenuation compromises HCL cell survival. Finally, we aim to pharmacologically disrupt these pro-survival pathways in HCL cells.
BRAF Inhibition as an Alternative to Chemotherapy in the Treatment Strategy of Hairy Cell Leukemia
Dr. Enrico Tiacci, University of Perugia, Perugia, Italy
Project Summary: Hairy cell leukemia (HCL) is very sensitive to chemotherapy, whose toxicity to the bone marrow and the immune system is however concerning. The investigators have established vemurafenib plus rituximab as a very effective chemotherapy-free regimen in relapsed/refractory HCL. Here, the investigators will test this regimen in a clinical trial against a chemotherapy-based standard of care represented by cladribine plus rituximab, aiming at lower toxicity and similar efficacy.
A Novel BAFF CAR-T for Treatment of Hairy Cell Leukemia
Dr. Reshmi Parameswaran, Case Western Reserve University School of Medicine, Cleveland, Ohio
Project Term: October 1, 2021 to September 30, 2023
Program Summary: Despite the success of Chimeric antigen receptor T cell (CAR-T) immunotherapies, disease relapse occurs in a majority of patients. We have developed a novel ligand based BAFF-CAR, that utilizes B cell activating factor (BAFF) as a ligand, which can bind to all three receptors of BAFF, which are expressed by malignant B cells including Hairy Cell Leukemia (HCL). We hypothesize BAFF CAR-T will be an effective therapeutic strategy for HCL.
Merging Immune and Molecular Signals in HCL for Improved Prognosis and Treatment Decision Making
Dr. David Ritchie, University of Melbourne
Project Term: October 1, 2021 - September 30, 2023
Project Summary: Our research consortium of diagnostic, translational and clinical researchers will undertake an integrated and novel exploration of the immune and genomic landscape in hairy cell leukemia (HCL) and correlate those data with response to both conventional and newly emerging therapies. We will apply our innovative platforms of digital spatial profiling, whole genome sequencing and circulating tumor DNA to provide highly novel data from our already collected sample bank from over 60 patients with HCL.
Lay Abstract: Hairy cell leukaemia (HCL) is a rare and slowly growing cancer of B lymphocytes. It has unique features and is often defined by the presence of a specific genetic change known as the BRAF V600E mutation. In some rare cases BRAF V600E mutations are not present and different genetic causes have been identified including our recently reported novel observation of an alternative type of BRAF alteration. For those patients with HCL that does not contain the BRAF V600E mutation there is a need to understand the precise genomic drivers of these atypical cases as those discoveries may critically inform personalized targeted treatment strategies.
Patients with HCL are commonly treated with cladribine (chemotherapy) and rituximab (an antibody targeting B cells) and often achieve complete and durable remission, however as many as 50% of patients experience disease relapse, requiring further treatment. Why some patients require recurrent therapy and others have long term remissions is unknown. We believe that understanding the genetics of the hairy cells and how the immune system responds to them may help answer this question. Our initial findings in the analysis of bone marrow samples taken before and after cladribine treatment has shown that patients with durable remissions have greater rates of immune recovery indicating that treatments that enhance immune recovery may allow long term remissions to be achieved. New molecularly-targeted therapies such as BRAF, MEK and BTK inhibitors provide non-chemotherapy options in HCL. The genomic mechanisms of resistance and the immune impact of these novel agents in HCL are largely unknown and may be of value for guiding subsequent therapy decisions.
This study proposes to further define the genomic and immune landscape of HCL as it relates to diagnosis, therapeutic decisions and disease monitoring in patients. Through this study we will develop and consolidate new discoveries via state-of-the-art genomic profiling and cutting edge immune profiling to help inform personalized treatment and optimize health outcomes.
Charting the Surfaceome to Eliminate Hairy Cell Leukemia (HCL)
Dr. Thorsten Zenz, Universitätsspital Zürich - Klinik für Medizinische Onkologie und Hämatologie USZ, Zurich
Project Term: October 1, 2021 to September 30, 2023
Program Summary: To optimize treatment of HCL, we dissect the tumors` surface proteome to understand a) surface mediated signals and b) the dependence on BRAFV600E activity, to c) eradicate remaining cell populations after BRAF inhibitor treatment. We use chemoproteomics, which enable mass-spectrometric-based surfaceome discovery to quantitatively investigate HCL. We expect to identify HCL specific and BRAF-dependent surfaceomes and identify new and critical targets for treatment.