Delivering unique immunotherapeutics for treatment of mantle cell lymphoma

Larry Kwak

PhD, MD

Beckman Research Institute of the City of Hope

Project Term: January 1, 2018 - December 31, 2022

Project Summary

City of Hope has a reputation for innovative translational research, and multiple researchers in the proposed application are prominent in the lymphoma field. The institutional commitment to translational science is evident in City of Hope’s investment in research support, regulatory affairs infrastructure, and campus clinical agent manufacturing facilities. Since patients with mantle cell lymphoma (MCL) have poor outcomes with standard therapies, our researchers have been developing MCL immunotherapies, which utilize the body’s immune defense mechanisms. Our projects are unified by a focus on targeting MCL cells using human antibodies or antibody fragments to specifically recognize molecules located on the surface of lymphoma tumor cells. In fact, 3 of the proposed agents to be tested in this grant were developed at City of Hope and will be manufactured here. The immunotherapies we propose target a range of MCL-associated molecules and employ novel mechanisms of action. Tumor target specificity is crucial to the safety and tolerability of any immunotherapy. To avoid severe side effects, the ideal target should be present only on MCL cells and not on normal cells. However even with perfect specificity, targeting a single molecule or cellular signaling pathway is frequently insufficient due to tumor escape mechanisms. Therefore we are exploring combining our antibody-based agents with commercial inhibitors of the B cell signaling pathways (BTK, PI3K, Akt) that allow lymphomas to grow and survive in an uncontrolled manner. We are also exploring combining agents between projects, in order to cut off tumor escape routes. Project 1: Development of a unique tumor-specific, antibody therapy against mantle cell lymphoma. Using a unique antibody discovery platform to target low-abundance, unique tumor cell markers, we have discovered an antibody fragment that binds specifically to human MCL cells. From this starting point, we engineered a modified antibody that binds highly specifically to MCL (MCL-Ab), with no binding to other subtypes of B-cell lymphomas, nor to normal blood cells or tonsil tissue. This MCL-Ab shows potent anti-tumor activity in mice with MCL. In Specific Aim (SA) 1, we will identify the MCL-Ab target molecule on the surface of MCL cells and confirm the antibody’s specificity for MCL (SA1). The MCL-Ab will then undergo optimization as a product for clinical use in humans as both a diagnostic test for confirming an MCL diagnosis (SA2) and as a potent, MCL-specific therapeutic agent (SA3). Clinical availability of an agent that is truly MCL-specific could be practice-changing in the treatment of this difficult disease. Project 2: Combining CAR T cells with signaling modulators for treatment of relapsed mantle cell lymphoma. Chimeric antigen receptor (CAR) T cell therapy is a promising new immunotherapy that reprograms a patient’s own immune T cells. T cells are isolated from a patient’s blood and genetically modified with an antibody-derived CAR that targets a specific tumor molecule, and then re-administered to the patient, where the engineered immune cells will recognize and kill tumor cells. CAR T cell therapy is less effective for lymphoma than for leukemia, so we propose combining CAR T cells with 3 oral agents that modulate immune B and T cell signaling: the BTK inhibitor ibrutinib, an Akt inhibitor, and a PI3K inhibitor. In SA1 we propose a clinical trial of ibrutinib for relapsed MCL, followed by CAR T cells that target the CD19 molecule on leukemia and lymphoma cells. We will also test the combined use of CD19 CAR T cells with MCL signaling pathway inhibitors, Akt and PI3K, to improve T cell persistence and potency (SA2). Finally, we plan to modify the MCL-Ab from Project 1 for use as a CAR, with the advantage of improved specificity for MCL (SA3). Project 3: Targeting oncogenic B cell receptor (BCR)-feedback control in refractory mantle cell lymphoma. Project 3 proposes to target the CD25 molecule that is exposed on the surface of both immune-inhibiting regulatory T cells (Tregs) and MCL cells, using a new CD25 antibody-drug conjugate (ADCT-301), in which the antibody component recognizes CD25 and delivers a potent poison directly to the target cell. In SA1, in a mouse strain with a human immune system, we will use the ADCT-301 to pre-deplete immune-suppressive Tregs and enhance the activity of Project 1’s MCL-Ab and Project 2’s CD19 CAR T cells. We have discovered that CD19 binding or PI3K/Akt inhibition can increase the amount of CD25 present on the MCL cell surface. In SA2, we will augment CD25 surface accumulation using Akt and PI3K inhibitors to maximize targeting by ADCT-301. In SA3, we will combine CD19 antibody or CD19 CAR T cells with ADCT-301 to enhance CD25 surface expression, and thus, ADCT-301 targeting. In funding year 4, we plan a clinical trial of ADCT-301 combined with inhibitor drugs or CD19 agents, depending on preclinical efficacy in SA2/3. Core A: Pathology and Tissue Bank Core. Core A will provide tissue sample banking services, screen the MCL-Ab for specificity and diagnostic utility (Project 1), characterize tumor samples for the clinical trial (Project 2), and assess the immune status of mice (Project 3). Core B: Translational Core. Core B will provide project management, clinical trial design, clinical protocol development, preparation of investigational new drug (IND) applications to the Food and Drug Administration (FDA), scientific writing, and regulatory support services. Altogether, we believe that these projects will increase our understanding of the complexities of MCL and its interaction with human immune defenses. We are also taking multiple approaches to bolstering those immune defenses to more effectively resist MCL. This grant application includes 2 clinical trials of our own novel agents combined with existing MCL signaling inhibitors. These strategies represent potential breakthroughs in MCL treatment and prevention of tumor escape.