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Tumor Immunotherapy

Tumor Immunotherapy

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.

Targeted Cancer Therapies

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...

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Generating potent and persistent antitumor immunity via affinity-tuned CAR-T cells targeting mesothelin.

Ya-Li Yue^1,2, Jun-Jun Liu^1,2, Hang Ma^1,2

¹School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.

Acta Pharmacologica Sinica

|May 9, 2025

Summary

Optimizing affinity-tuned chimeric antigen receptor (CAR)-T cells targeting mesothelin (MSLN) improved solid tumor treatment. The LP12 CAR-T variant demonstrated potent efficacy, long-term persistence, and prevented recurrence without toxicity.

Keywords:

LP12 CAR-T cells affinity-tuned chimeric antigen receptor mesothelin solid tumors tumor recurrence

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Area of Science:

Immunology
Oncology
Biotechnology

Background:

Chimeric antigen receptor (CAR)-T cell therapy shows promise for solid tumors but faces challenges in efficacy and recurrence.
Mesothelin (MSLN) is a tumor-associated antigen with restricted expression in normal tissues, making it a viable target for CAR-T therapy.
Previous work involved affinity maturation of the parental antibody M912 to develop novel anti-MSLN antibodies.

Purpose of the Study:

To develop novel, high-affinity human antibodies targeting mesothelin (MSLN).
To construct and evaluate third-generation CAR-T cells utilizing these antibodies for solid tumor treatment.
To assess the in vitro and in vivo efficacy, safety, and persistence of affinity-tuned MSLN-targeted CAR-T cells.

Main Methods:

Phage display library construction and affinity maturation to identify anti-MSLN antibodies (LP12, HP4-11, HP4-41/LP6, HP4-44/LP2).
Generation of lentiviral vectors to produce third-generation CAR-T cells targeting MSLN.
In vitro assays for cytolytic activity, cytokine production, and proliferation; in vivo studies in mice with disseminated MSLN-positive tumors.

Main Results:

Four novel human anti-MSLN antibodies with enhanced affinity were identified.
Generated CAR-T variants exhibited robust cytolytic activity, cytokine release, and proliferation against MSLN-positive tumors in vitro.
The LP12 CAR-T variant demonstrated potent eradication of disseminated tumors in mice, long-term in vivo persistence, recurrence prevention, and no observed off-tumor toxicity.

Conclusions:

Optimizing CAR antigen-binding domain affinity is a promising strategy for developing effective and safe CAR-T cell therapies for solid tumors.
The affinity-tuned LP12 CAR-T cells show significant potential for treating MSLN-positive solid tumors.
This approach offers a potential solution to overcome current limitations of CAR-T cell therapy in solid malignancies.