Individual Final Project

Logic_Gated_Symbols Logic_Gated_Symbols

title: Week 1 Principles and Practices weight: 10 description: Project Proposal Logic-Gated CAR-NK Therapies for Solid Tumors

Final Project Proposal

The Concept Logic-Gated CAR-NK

My interest lies in the design of Logic-gated CAR-NK therapies specifically for solid tumors. While CAR-T therapies have revolutionized hematological cancer treatment, they struggle in solid tumors due to the hostile microenvironment and antigen heterogeneity.

The Solution

Using Boolean Logic Gates (AND, OR, NOT), we can program cellular behavior:

  • AND Gate: Cell attacks only if two specific antigens are present.
  • NOT Gate: Attack stops if a healthy tissue marker is detected.
  • Manufacturing: Using allogenic sources (cord blood or iPSCs) for off-the-shelf availability.

AI and Governance Framework

Core Goal

Ensure safety and accessibility in the deployment of advanced cellular therapies.

Sub-goal 1 Prevent On-Target Off-Tumor Toxicity

  • Risk: Attacking healthy organs expressing low levels of target antigen.
  • Requirement: Logic gates must reliably distinguish malignant cells from healthy tissues.

Sub-goal 2 Democratize Access via Scalable Manufacturing

  • Current State: Autologous CAR-T is bespoke and highly expensive.
  • Policy Goal: Establish regulatory frameworks that support scalable, allogeneic manufacturing to reach non-elite medical centers.

Governance Actions

Action A Standardization of Logic-Gate Stress-Testing

Current testing for CAR-T occurs in idealized laboratory conditions. We need regulatory stress testing under stimulated Tumor Microenvironment Conditions.

  • Purpose: Ensure the OFF switch does not fail under physiological stress.
  • Design: IND reviews must show that gates function under exhaustion or immunosuppression.
  • Assumption: TME models like 3D organoids accurately predict human biological interactions.
  • Risk of Failure: Gates might work in the model but fail in the patient due to antigen shifts.

Action B Mandatory Long-Term Registry

A centralized 5-year patient registry is needed to track gene therapy risks.

  • Purpose: Track long-term risks such as insertional mutagenesis.
  • Success Consequence: Detecting rare side effects could lead to necessary class-wide suspensions.
  • Failure Mode: Incomplete data leads to unnoticed safety signals.

Policy Scoring Matrix

Enhance Biosecurity

  • By preventing incidents: Score 3
  • By helping respond: Score 3

Foster Lab Safety

  • By preventing incidents: Score 2
  • By helping respond: Score 2

Feasibility and Cost

  • Minimizing burdens: Score 3
  • Feasibility: Score 2
  • Promote application: Score 2