CAR-T Generations: A Practical Guide for Strategic Acquirers
Separating Innovation from Marketing
Article 6 of 10 in a series on cell therapy partnership strategy.
Every cell therapy company claims next-generation technology. Marketing materials describe "fourth-generation CARs," "armored CARs," and proprietary enhancements. For strategic acquirers, the challenge is separating genuine innovation from incremental modification.
The Generational Framework
CAR-T generations are defined by the intracellular signaling domains that determine how T-cells respond when the CAR engages its target.
First generation: Single signaling domain (typically CD3ζ). These CARs could redirect T-cell killing but lacked persistence. Cells activated, killed target cells, but exhausted rapidly. First-generation CARs are largely historical.
Second generation: Added a costimulatory domain (CD28 or 4-1BB) alongside CD3ζ. This combination enabled sustained T-cell activation and persistence. All currently approved CAR-T products are second-generation.
Third generation: Combined two costimulatory domains with CD3ζ. Clinical data has been mixed—additional costimulation doesn't reliably improve efficacy and may increase toxicity.
Fourth generation (TRUCKs/Armored CARs): Added gene expression capability beyond signaling—typically cytokine secretion to enhance anti-tumor activity. Clinical validation is ongoing.
What Actually Matters for Persistence
Generation number is less predictive of clinical success than specific design choices:
Costimulatory domain selection. 4-1BB costimulation consistently produces longer CAR-T persistence than CD28 in clinical data. The 4-1BB versus CD28 choice is a more reliable persistence predictor than generation number.
Manufacturing phenotype. The T-cell phenotype at infusion correlates strongly with persistence. A well-manufactured second-generation CAR may outperform a poorly-manufactured fourth-generation CAR.
Tonic signaling management. Some CAR designs exhibit constitutive activation even without target engagement. This drives T-cell exhaustion. Managing tonic signaling is often more important than adding signaling domains.
"A well-manufactured second-generation CAR may outperform a poorly-manufactured fourth-generation CAR. Generation number is not a quality indicator."
Innovations That Matter: Clinical Validation Required
Strategic acquirers should apply skepticism to preclinical innovation claims.
Armored/TRUCK CARs. Cytokine-secreting CARs have strong preclinical rationale, particularly for solid tumors. Clinical data is emerging but not yet definitive.
Logic-gated CARs. "AND" gates and "NOT" gates address specificity concerns. Clinical data remains limited, and the engineering complexity adds manufacturing challenges.
Dual-targeting CARs. CARs targeting two antigens simultaneously aim to prevent antigen-escape relapse. Clinical data supports the concept—this represents genuine clinical validation of a next-generation approach.
Diligence Framework
When evaluating next-generation CAR-T opportunities:
Clinical validation stage. Is the innovation validated in patients, or only in preclinical models?
Comparator data. Compared to what? Claims require comparison to current standard-of-care.
Manufacturing complexity. Does the innovation work with rapid manufacturing, or does it require extended production times?
Regulatory pathway clarity. Has the company engaged with FDA/EMA on the pathway?
IP position. Freedom-to-operate analysis is essential before valuing proprietary next-generation technology.
Strategic Positioning
Second-generation CARs remain the validated workhorse. Investments in next-generation technology should be evaluated as options—potentially valuable if clinical validation emerges, but carrying meaningful development risk.
Most importantly, generation number should never substitute for rigorous clinical and manufacturing diligence. The best CAR is the one that gets manufactured well, reaches patients quickly, and persists long enough to produce durable responses.
Next in series: Solid Tumor CAR-T
Previous: Speed-to-Patient as Competitive Advantage
For advisory on cell therapy partnership strategy, contact Kerlann Advisory.