Researchers at Johns Hopkins University School of Medicine have developed a new class of bifunctional antibody-based immunotherapy that targets immune checkpoints, but simultaneously disables the production of immunosuppressive regulatory T cells (Tregs). The new molecules, dubbed Y-traps, comprise a Y-shaped antibody fused to a transforming growth factor beta (TGF-β) receptor domain that switches off the ability of TGF-β to trigger Tregs.
Reporting in Nature Communications, the team describes the development of Y-traps targeting either cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1), which are targets of clinically approved monoclonal antibody-based immunotherapies. When tested in mouse models of human cancer, the Y-traps slowed the growth of tumors that were resistant to their respective marketed antibodies ipilimumab, which targets CTLA-4, and atezolizumab and avelumab, which target PD-L1. “Tregs have long been a thorn in the side of cancer immunotherapy,” says Atul Bedi, M.D., associate professor of otolaryngology at the Johns Hopkins School Medicine and senior author of the team’s published paper (“Bifunctional Immune Checkpoint-Targeted Antibody-Ligand Traps That Simultaneously Disable TGFβ Enhance the Efficacy of Cancer Immunotherapy”). “We've finally found a way to overcome this hurdle with this CTLA-4-targeted Y-trap.”
The CTLA-4 blocking antibody, ipilimumab, two PD-1 antagonists (pembrolizumab and nivolumab), and three PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab) have been approved for the immunotherapy of specific cancers, including melanoma, non-small-cell lung cancer, head and neck cancer, and bladder cancer. Unfortunately, while some patients treated with checkpoint inhibitors will experience long-lasting remission or prolonged survival, most cancers will fail to respond, the authors write. “Monoclonal antibodies that block these immune checkpoints can unleash antitumor immunity and produce durable clinical responses in a subset of patients with advanced cancers, such as melanoma and non-small-cell lung cancer. However, these immunotherapeutics are currently constrained by their inability to induce clinical responses in the vast majority of patients.”
Cancers frequently express TGF-β, which drives immune dysfunction by inducing the production of immune suppressive Tregs in the tumor microenvironment. The Johns Hopkins researchers suggest that one of the key limitations of checkpoint inhibitors is that they don’t address key molecular determinants that are responsible for promoting such immune dysfunction. “Our data indicate that elevated expression of TGF-β expression is a root cause” of T-cell dysfunction in the tumor microenvironment,” they state.
The researchers hypothesized that switching off Tregs could help existing immunotherapies to work better. “This is especially challenging because Tregs are not only induced by the TGF-β protein made by tumor cells, but make their own TGF-β to maintain their identity and function in the tumor,” says Dr. Bedi. Tregs, in addition, produce CTLA-4, which also prevents antitumor immune cells from acting.
As a new approach to disabling Tregs and boosting immunotherapy effectiveness, the team generated two Y-traps, one targeting CTLA-4, and a separate Y-trap targeting PD-L1. Both molecules included a receptor domain to trap TGF-β. When tested in experimental mice engineered with human immune cells, and carrying human melanoma tumors, the Y-traps inhibited tumor-infliltrating Tregs and were more effective than existing immune checkpoint inhibitors at inhibiting tumor progression.
“Our data demonstrate that Y-traps counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors,” the authors state.
They acknowledge that translating their developments into the clinic will require the design of careful dose-escalation trials to determine safety and maximum tolerated and optimum therapeutic dose and frequency, so that antitumor immune responses are elicited without triggering immune-related adverse events. Nevertheless, they say, “As elevated TGFβ is an especially common denominator of immune dysfunction in many types of cancer, these Y-traps may provide an effective immunotherapeutic strategy against cancers that fail to respond to current immune checkpoint inhibitors by simultaneously disabling immune checkpoints and counteracting TGFβ-mediated immune tolerance.”
“These first-in-class Y-traps are just the beginning,” notes Dr. Bedi. “We have already invented a whole family of these multifunctional molecules based on the Y-trap technology. Since mechanisms of immune dysfunction are shared across many types of cancer, this approach could have broad impact for improving cancer immunotherapy. Y-traps could also provide a therapeutic strategy against tumors that resist current immune checkpoint inhibitors.”