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Tumor Immunotherapy

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Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.

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Overcoming Immune Checkpoint Inhibitor Resistance with Potent, Selective Dual αvβ6/8 Inhibitors Based on Engineered

Anna Lechner¹, Peter A Jordan¹, Gabriella Costa Machado da Cruz¹

¹Lassogen, Inc., 3830 Valley Centre Drive, Suite 705-562, San Diego, California 92130, United States.

Journal of the American Chemical Society

|September 2, 2025

Summary

This summary is machine-generated.

Dual integrin inhibitors designed using lasso peptides can overcome resistance to immune checkpoint inhibitors by targeting TGF-β in the tumor microenvironment. This approach halts tumor growth and regression in preclinical models.

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Initial Evaluation of Antibody-conjugates Modified with Viral-derived Peptides for Increasing Cellular Accumulation and Improving Tumor Targeting

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Published on: March 8, 2018

Area of Science:

Oncology
Immunology
Biotechnology

Background:

Integrins αvβ6 and αvβ8 activate immunosuppressive TGF-β in the tumor microenvironment (TME).
This activation is a key mechanism of resistance to immune checkpoint inhibitors (ICIs) in various cancers.

Purpose of the Study:

To engineer potent and selective dual αvβ6/8 integrin inhibitors using lasso peptides.
To demonstrate the therapeutic potential of these inhibitors in overcoming ICI resistance.

Main Methods:

Epitope scanning, computational design, and directed evolution were used to engineer dual αvβ6/8 inhibitors.
Lasso peptides were conjugated with albumin binders to extend half-life.
NMR structures of inhibitors were determined.

Main Results:

Engineered lasso peptides potently and selectively inhibited αvβ6/8 integrins.
Half-life extended analog 19 halted tumor growth and regressed tumors in anti-mPD-1-resistant ovarian and triple-negative breast cancer models when combined with ICIs.
Lasso peptides demonstrated drug-like properties, including tunable pharmacokinetics and efficacy.

Conclusions:

Dual inhibition of αvβ6/8 integrins is a promising tumor-specific strategy to overcome TGF-β-driven ICI resistance.
Lasso peptides represent a versatile and effective platform for developing novel cancer therapeutics.
This work enables future advances in lasso peptide-based drug development.