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<p>The persistence of CAR T cells and antigen escape remain major barriers to durable therapeutic success in hematologic malignancies. Our study integrates AI-guided design with targeted protein degradation to overcome these challenges. Utilizing an in-silico library of CAR constructs followed by an in vitro screening, we developed a predictive model, CARMSeD, which forecasts constructs prone to self-activation and dysfunction. Optimized bispecific CD20/CD19 CAR T cells demonstrate superior persistence and anti-tumor efficacy. To further improve durability, the platform incorporates a PROTAC-based module that selectively degrades AKT3, promoting FOXO4-driven mitochondrial fitness, central memory differentiation, and reduced mTOR signaling. We extended this strategy to develop a trispecific CAR T platform co-expressing a secretable CD3/CD22 bispecific engager, achieving potent tumor eradication even in CD19/CD20-negative malignancies demonstrates efficacy across patient-derived leukemia samples and solid tumor models. Together, our study introduces a next-generation AI-guided CAR T strategy that integrates structure-based optimization and intracellular modulation to improve persistence, broaden antigen coverage, and ensure durable therapeutic efficacy.</p>

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AI-guided CAR designs and targeted pathway modulation to enhance multi-antigen CAR T cell durability and overcome antigen escape

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月17日

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  • Mohammad Sufyan Ansari,
  • Varnit Chauhan,
  • Aashi Singh,
  • Areej Akhtar,
  • Nisha Chaudhary,
  • Reegina Tyagi,
  • Divya,
  • Kashif Husain,
  • Sheetal Sharma,
  • Ruquaiya Alam,
  • Md Shakir,
  • Mehak Pracha,
  • Samreen Anjum,
  • Mohd Nadeem,
  • Prial Taneja,
  • Md Imam Faizan,
  • Iqbal Azmi,
  • Aditya Ramdas Iyer,
  • Pragya Gupta,
  • Mehwish Nafiz,
  • Shayan Ali,
  • Insha Mohi Uddin,
  • Momina Javid,
  • Zahoor Ahmad Bhat,
  • Hamenth Kumar Palani,
  • Amit Kumar Srivastava,
  • Ulaganathan Mabalirajan,
  • Vikram Mathews,
  • Mohammad Husain,
  • Sivaprakash Ramalingam,
  • Gaurav Kharya,
  • Tanveer Ahmad

摘要

The persistence of CAR T cells and antigen escape remain major barriers to durable therapeutic success in hematologic malignancies. Our study integrates AI-guided design with targeted protein degradation to overcome these challenges. Utilizing an in-silico library of CAR constructs followed by an in vitro screening, we developed a predictive model, CARMSeD, which forecasts constructs prone to self-activation and dysfunction. Optimized bispecific CD20/CD19 CAR T cells demonstrate superior persistence and anti-tumor efficacy. To further improve durability, the platform incorporates a PROTAC-based module that selectively degrades AKT3, promoting FOXO4-driven mitochondrial fitness, central memory differentiation, and reduced mTOR signaling. We extended this strategy to develop a trispecific CAR T platform co-expressing a secretable CD3/CD22 bispecific engager, achieving potent tumor eradication even in CD19/CD20-negative malignancies demonstrates efficacy across patient-derived leukemia samples and solid tumor models. Together, our study introduces a next-generation AI-guided CAR T strategy that integrates structure-based optimization and intracellular modulation to improve persistence, broaden antigen coverage, and ensure durable therapeutic efficacy.