Scientists from Johns Hopkins, using software from Insilico Medicine, say they have invented a new class of immunotherapeutics to fight cancer. The team published its study (“Bifunctional Immune Checkpoint-Targeted Antibody-Ligand Traps That Simultaneously Disable TGFβ Enhance the Efficacy of Cancer Immunotherapy”) in Nature Communications.

“A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH1 cells. To address this therapeutic challenge, we invent bifunctional antibody–ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd). a-CTLA4-TGFβRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, a-PDL1-TGFβRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab),” write the investigators.

“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 researchers found that TGFβ pathway activation in various cancers is highly correlated with FOXP3, the signature of Tregs. Tumors are frequently infiltrated by Tregs, and this is strongly correlated with poor outcome in multiple cancer types.

To sequester TGFβ, they engineered a trap based on the natural receptor to TGFβ. They created two different types of Y-traps: one consisting of a CTLA-4 antibody fused to a TGFβ trap, and another consisting of a PD-L1 antibody fused to a TGFβ trap.

The researchers used the CTLA4-targeted Y-trap to specifically turn off and delete Tregs. “This Y-trap not only disables CTLA-4 function, but it also disrupts the TGFβ feedback loop that is necessary for induction and maintenance of Tregs in the tumor,” says Atul Bedi, M.D., associate professor at Johns Hopkins University School of Medicine and senior author of the study.

While the clinically used CTLA-4 antibody ipilimumab could not decrease Tregs in these tumors, the CTLA4-targeted Y-trap was strikingly effective at reducing Tregs and activating antitumor immunity. Most significantly, the Y-trap was effective at inhibiting the growth and spread of tumors that were unresponsive to treatment with ipilimumab and pembrolizumab, a PD-1 antibody used in the clinic.

Antibodies to another immune checkpoint, PD-1, or its ligand (PD-L1), are approved for treatment of many advanced cancers. However, fewer than 20% of patients respond in most tumor types. “We hypothesized that TGFβ limits the efficacy of antibodies against PD-L1, so we designed a Y-trap that simultaneously counteracts both these axes of immune suppression in the tumor,” Dr. Bedi says.

Indeed, Dr. Bedi and colleagues demonstrated that the PD-L1 targeted Y-Trap is significantly more effective in inhibiting tumor growth compared to the clinically used PD-L1 antibodies atezolizumab and avelumab. Moreover, the PD-L1-targeted Y-trap was able to curtail the growth of tumors that do not respond to PD-L1 or PD-1 antibodies.

Dr. Bedi's team has invented a family of multifunctional molecules based on the Y-trap platform, which has been licensed from Johns Hopkins to Y-Trap, a company that is advancing its development for different cancer treatment scenarios.

“Since these mechanisms of immune dysfunction are shared across many types of cancer, the Y-trap approach could have broad impact for improving cancer immunotherapy,” notes Dr. Bedi.

“This approach appears to be an innovative strategy, and an exciting technical accomplishment to target multiple suppressive mechanisms in the tumor microenvironment,” adds Robert Ferris, M.D., Ph.D., professor of oncology at the University of Pittsburgh, who was not connected with the study. “I look forward to seeing its translation into the clinic.”

Dr. Bedi envisions using Y-traps not only for treatment of advanced, metastatic disease, but also in the neoadjuvant setting to elicit a vaccine effect, i.e., giving them to patients before surgery to prevent recurrence of the disease.

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