Multiple myeloma (MM) is a malignant hematologic tumor originating from plasma cells. Despite significant advances in available therapies, disease relapse and drug resistance remain major barriers to achieving a cure. The exceptionally high genetic and phenotypic heterogeneity of MM enables tumors to rapidly develop adaptive immune escape mechanisms in response to therapies that rely on a single target—most commonly through downregulation or complete loss of the target antigen. As a result, even cutting-edge immunotherapies such as bispecific antibodies and CAR T cells are at risk of therapeutic failure. Therefore, developing next-generation immunotherapy platforms that can dynamically adapt to antigenic changes while maintaining both precision and breadth is critical to overcoming current treatment limitations.
A research team led by Shannuo Li at the University of Utah aims to address this challenge. Their work introduces an innovative modular therapeutic strategy designed to provide a more robust and flexible immunotherapy solution for multiple myeloma.
Interview with Shannuo Li
Hematology Frontier
Shannuo Li: Our research focuses on developing a novel precision immunotherapy strategy for multiple myeloma. MM remains an incurable hematologic malignancy, largely due to its profound tumor heterogeneity and its tendency to develop resistance to single-target therapeutic approaches. Many current immunotherapies—including bispecific antibodies and CAR T cells—depend on targeting a single antigen. Tumor cells can evade immune attack by downregulating or completely losing that antigen, leading to immune escape.
To address this problem, our team proposed a modular platform termed the Self-assembled Immune cell Tumor Engager (SITE). This platform is essentially a two-component system. One component is designed to target tumor-associated antigens, such as BCMA, CD38, or GPRC5D expressed on multiple myeloma cells. The other component binds to specific markers on immune effector cells, such as CD3 on T cells, NKG2D on NK cells, or CD89 on macrophages.
Each component is conjugated to complementary morpholino oligonucleotides. When these two components encounter each other in vivo, they undergo hybridization-driven self-assembly, forming a biologically active immune engager directly at the tumor site. This newly assembled molecule bridges tumor cells and immune cells, effectively triggering immune-mediated cytotoxic killing of tumor cells.
We validated the strong antitumor activity of the SITE platform across multiple experimental settings, including cell culture systems, in vivo mouse models, and ex vivo patient-derived samples. We believe that this modular, self-assembling strategy represents a promising direction for the development of next-generation immunotherapies. Such therapies have the potential to be more robust, safer, and better suited to the real-world complexity of cancer.
Summary
This study establishes and validates the SITE modular platform, offering an innovative approach to addressing tumor heterogeneity and antigen escape in multiple myeloma. The core strength of the SITE platform lies in its “on-demand self-assembly” design. By decoupling tumor targeting and immune cell recruitment into independent modules, SITE enables precise, localized assembly and functional activation of therapeutic components directly at the tumor site.
Preclinical studies demonstrate that this strategy can effectively mediate potent antitumor activity. Conceptually, SITE moves beyond the limitations of traditional “fixed-target” approaches and represents a shift toward programmable and adaptive immunotherapy. In the future, by integrating a broader range of tumor-targeting and immune-effector modules, the SITE platform could evolve into a universal immunotherapy framework. Its applications may extend beyond multiple myeloma to other hematologic malignancies and solid tumors, highlighting its significant translational and clinical potential.
Research Abstract
915: Precision Immunotherapy for Multiple Myeloma Using Morpholino Oligonucleotide–Guided Self-Assembled Immune Cell–Tumor Engagers (SITE)
Bispecific T-cell engagers have demonstrated substantial clinical efficacy and have received FDA approval for the treatment of relapsed/refractory multiple myeloma (RRMM). However, challenges remain, including limited targeting flexibility, immune-related toxicities, and lack of durable responses. To overcome these limitations, we developed Self-assembled Immune cell Tumor Engagers (SITE).
SITE is a two-component system capable of simultaneously targeting immune cells and MM cell surface antigens. Each component is labeled with complementary morpholino oligonucleotides (M1 or M2). Following administration, the components hybridize in situ via M1–M2 pairing to form a bispecific complex that redirects immune cells toward MM cells.
This pre-targeting strategy allows for the sequential recruitment of multiple immune effector cell types, including T cells, NK cells, and macrophages. Moreover, simultaneous targeting of multiple antigens (e.g., BCMA, GPRC5D, and CD38) minimizes the risk of antigen loss and immune escape.
We report the efficacy of SITE across multiple models, including in vitro cell lines, ex vivo patient-derived samples, and in vivo mouse models. Our results demonstrate that SITE is an innovative and cost-effective platform capable of orchestrating coordinated and potent antitumor immune responses.
Anti-MM antibodies were enzymatically digested into F(ab′)₂ fragments and further reduced with tris(2-carboxyethyl)phosphine to generate Fab′MM-thiol. A pair of 25 bp M1/M2 oligonucleotides was custom synthesized by Gene Tools. After 3′-end maleimide modification, Fab′MM–M1 conjugates targeting BCMA, GPRC5D, and CD38 were generated. Similarly, Fab′immune–M2 conjugates targeting immune cells were produced using anti-human CD3 and anti-human CD314 antibodies.
The stability of M1–M2 hybrids was evaluated using circular dichroism spectroscopy in PBS and size-exclusion chromatography after incubation in mouse serum. Primary human T cells and NK cells were isolated from healthy donors. SITE-mediated cytotoxicity and immune activation were assessed by flow cytometry using MM.1S and RPMI-8226 cells. Therapeutic efficacy was further evaluated using patient-derived bone marrow mononuclear cells and a preclinical NRG mouse model.
Compared with teclistamab, SITE-treated mice bearing MM.1S-Luc tumors exhibited prolonged survival and suppressed tumor growth. Bone marrow flow cytometry confirmed a significant reduction in MM cells. T cell–related toxicity correlated with the number of infused T cells, and reducing the dose eliminated weight loss, highlighting the flexibility of the two-component SITE system.
Overall, SITE demonstrated superior antitumor efficacy compared with teclistamab, underscoring its powerful in vivo control of MM progression.
The SITE platform represents a promising advancement in MM immunotherapy, offering a versatile, potent, and modular approach to addressing the disease’s complex antigen landscape. By enabling multi-antigen targeting and coordinated engagement of diverse immune effector cells, SITE effectively overcomes challenges such as antigen heterogeneity, immune escape, and cytokine release syndrome.
Expert Profile
Shannuo Li University of Utah
PhD candidate in Molecular Pharmaceutics at the University of Utah. She received her Master’s degree in Drug Discovery and Development from Uppsala University in 2022. Her research interests include pharmacokinetics of drug delivery across the blood–brain barrier. Her doctoral research will focus on drug-free macromolecular therapies and drug conjugates for Alzheimer’s disease.
