Harnessing The Power Of Our Immune Systems To Transform Patient Outcomes In Multiple Myeloma

By Luke Walker, M.D., Chief Medical Officer of Harpoon Therapeutics

Over the last decade, the emergence of immunotherapies has radically changed the treatment landscape for oncologists and their patients. Beginning in 2011 with the U.S. Food and Drug Administration (FDA) approval of ipilimumab for unresectable or metastatic melanoma, immune checkpoint inhibitors that target specific markers on tumor cells, allowing the patient’s own immune system to attack them, have become one of the most effective approaches, alone or in combination with conventional therapies (e.g., radiation, chemotherapy and other targeted therapies) or newer immunotherapies (e.g., cancer vaccines, oncolytic viruses),¹ to treat a broad range of solid tumors.

More recently, chimeric antigen receptor T (CAR T)-cell therapies have shown promise in treating many cancer types, most notably hematological malignancies, such as multiple myeloma. With CAR T-cell therapies, T cells are taken from the patient's blood and are altered in the laboratory by adding a gene for a receptor – a chimeric antigen receptor – which helps the T cells attach to a specific cancer cell antigen. The CAR T cells are then given back to the patient, where the CAR T cells expand in number and bind with cancer cells to destroy them.²

Although T cells are the immune system’s killer cells, best specialized to combat virally infected cells and malignant cells, challenges remain in how best to exploit them in a controlled therapeutic setting. Providing additional effective and tolerable immunologic-based therapies beyond CAR T-cell therapy and immune checkpoint inhibitors remains a high priority for the scientific community, particularly given the limitations of tolerability for many patients with advanced disease.

New Research Avenues to Maximize the Power of T Cells

T cell engagers, or T cell-engaging antibodies, are emerging as a potent tool against both solid tumors and hematologic malignancies. Many tumor cells develop mechanisms that help them to evade recognition by the patient’s T cells to avoid detection and destruction by the body’s immune defenses. T cell engagers are engineered proteins that redirect T cells to attack these evasive tumor cells by physically connecting a T cell to tumor cells. These T cells may not recognize tumor cells as “foreign,” and the T cell engager redirects the T cell to targets on the tumor cell, allowing the T cell to be activated to kill the malignant cell. T cell engagers thus work as adaptors that transiently connect T cells with their target cells for redirected tumor cell lysis.³

A key challenge with the use of T cell engagers and CAR T, to date, has been treatment-related adverse events, which often limit dosing amount and frequency, impacting the ability to maximize efficacy. Given these limitations, there is a significant need for T cell engagers with a wider therapeutic window that can more capably balance efficacy and tolerability to help a greater number of patients.⁶

A number of companies are exploring new approaches to the development of T cell engagers that aim to enhance their therapeutic benefits while minimizing adverse events. For instance, at Harpoon Therapeutics, we are currently leveraging three distinct T cell engager platforms that allow for the development of “off-the-shelf” T cell-directed therapies to a broad set of tumor targets and clinical indications, thus creating an opportunity to address the needs of many patients. The company’s foundational Tri-specific T cell Activating Construct (TriTAC^®) platform, a novel antibody-based drug discovery platform, may offer a new way to unleash the target cell-killing properties of a patient’s own immune system.4 The goal is to minimize off-target toxicities, particularly cytokine release syndrome, and to widen the therapeutic window by offering greater tolerability, with potential uses in hematologic malignancies as well as solid tumors.⁶

A Potential Path to Addressing Unmet Needs in Multiple Myeloma

Multiple T cell engagers to date have demonstrated meaningful activity in patients with blood cancers like multiple myeloma. Despite significant treatment advances in recent years, serious unmet medical need remains in the treatment of multiple myeloma, particularly for patients with relapsed or refractory multiple myeloma (RRMM) who have received multiple lines of therapy and still face progressing disease. While treatment advances have led to an increase in the five-year relative overall survival rate from 34.6% to 53.9% over the last 25 years,⁴ tolerability issues and long-term adverse events are common with current treatments, and there continues to be a need for effective and safe solutions that extend survival without severely impacting a patient’s quality of life.⁵

One emerging approach to the treatment of multiple myeloma is the use of immunotherapy via T cell activation targeted against B-Cell Maturation Antigen (BCMA), a cell surface protein. BCMA was first identified as a prognostic marker in multiple myeloma more than two decades ago and, starting in 2014, the first use of BCMA as a treatment target was evaluated in patients with multiple myeloma who received CAR T cells. Today, a range of myeloma treatments target BCMA, including CAR T cells, along with antibody drug conjugates and bispecific antibodies; some agents are in development, and some have been approved by the FDA.⁶

Recently, bispecific T cell engager therapy, targeting BCMA and CD3 antigens on myeloma cells and T cells, respectively, have shown promising results in in RRMM, both in preclinical and clinical studies and in practice. BCMA-targeted therapy represents a transformational shift in how the oncology community approaches treatment of this disease and it is quickly becoming a pillar of RRMM therapy.

To date, three cell therapies that target BMCA have been approved for RRMM: iIdecabtagene vicleucel (Abecma^®); ciltacabtagene autoleucel (Carvykti™); and teclistamab-cqyv (Tecvayli™); teclistamab-cqyv was the first bispecific t-cell engager to be approved by the FDA for patients with RRMM. Harpoon Therapeutics’ investigational T cell engager, HPN217, is a novel BCMA-targeting TriTAC in development for the treatment of RRMM, in patients who have received at least three prior therapies. Updated interim results of an ongoing Phase 1 study were recently presented at the American Society of Hematology 2022 annual meeting, with HPN217 demonstrating early clinical activity and durable responses, including a 77% (10/13) objective response rate (ORR) observed across the highest doses (12 and 24 mg). Additionally, 86% (18/21) of responders remained on study treatment with sustained response, with many responders on treatment for over a year. Importantly, HPN217 was generally well-tolerated across a wide dose range in patients with RRMM, with a low incidence of cytokine release syndrome (CRS). Dose and schedule optimization is ongoing with maximum tolerated dose not yet reached in step dose regimen.⁷

Hope for the Future of Treating Relapsed/Refractory Multiple Myeloma

Twenty years ago, there were far fewer therapies available to treat multiple myeloma – and even in settings in which treatment was possible, these therapies would often fail patients quickly. With novel technology platforms and innovative research methods at our disposal, we have reached a point where significant progress has been made in delivering a greater number of treatment options for patients with this devastating disease. Now, while continued research is needed, we are on the cusp of delivering new therapies that could also provide deep and durable responses over time.

Bispecific T cell engagers targeting BCMA represent a potential new therapeutic modality in the fight against cancers like multiple myeloma. Our key challenges lie in determining optimal dosing that will prove efficacious without sacrificing safety and tolerability, leading to successful outcomes over time. The research avenues in front of us are promising – and I have never felt more hopeful for what’s to come.