Solid Tumor CAR-T

What Early Movers Are Getting Right

Article 7 of 10 in a series on cell therapy partnership strategy.

Autologous CAR-T has achieved complete response rates exceeding 70% in certain hematologic malignancies. In solid tumors, the same fundamental technology has struggled to achieve double-digit response rates. The gap represents both the field's greatest failure and its largest remaining opportunity.

The challenges are well-documented: hostile tumor microenvironments that suppress T-cell function, physical barriers that prevent T-cell infiltration, antigen heterogeneity that enables tumor escape, and on-target off-tumor toxicity from antigens expressed on normal tissues. After a decade of effort, no solid tumor CAR-T has achieved regulatory approval.

Yet within the overall disappointment, specific approaches show genuine promise.

The Delivery Revolution

The most consistent predictor of solid tumor CAR-T activity is not the construct design—it's the delivery route. Regional administration directly to tumor sites produces response rates that intravenous delivery cannot match.

The data is striking. CEA-targeting CAR-T delivered intravenously to colorectal cancer patients achieved minimal responses. The same construct delivered via hepatic artery infusion for liver metastases showed objective response rates around 25%. GD2-targeting CAR-T for brain tumors administered intravenously showed limited activity; intraventricular delivery to CNS tumors has produced meaningful responses including durable complete remissions in individual cases.

"Regional delivery doesn't solve the solid tumor problem, but it's the most validated approach for improving the odds."

For strategic acquirers, programs that incorporate regional delivery strategies—intraperitoneal for ovarian cancer, intratumoral for accessible tumors, intraventricular for CNS malignancies—merit different probability-of-success assumptions than programs relying solely on intravenous administration.

Tumor Microenvironment Engineering

The solid tumor microenvironment actively suppresses T-cell function through multiple mechanisms. Next-generation CARs specifically engineered to resist these suppressive signals represent the most active area of innovation:

TGF-β resistance. CARs incorporating dominant-negative TGF-β receptors maintain function in TGF-β-rich environments.

Checkpoint resistance. PD-1 knockout CARs prevent the checkpoint-mediated suppression that solid tumors use to inactivate T-cells.

Armored CARs. CARs that secrete cytokines upon activation can modify the local microenvironment. Clinical data is emerging—the approach shows activity but raises safety questions.

Target Selection: The Safety-Efficacy Balance

Solid tumor CAR-T target selection faces a fundamental challenge. The targets showing clinical activity share characteristics that manage this risk:

Tumor-restricted expression patterns. GD2 in neuroblastoma, mesothelin in mesothelioma and ovarian cancer.

Accessible normal tissue. CEA is expressed in normal GI epithelium, but this tissue can be managed with supportive care.

Density differential. Targets where tumor expression dramatically exceeds normal tissue expression allow for CAR affinity tuning.

Strategic Positioning

For acquirers considering solid tumor opportunities:

Favor regional delivery programs. The clearest signal for improved activity comes from regional administration.

Prioritize tumor-restricted targets. Target safety is a gate criterion. No amount of engineering innovation compensates for a target with dangerous normal tissue expression.

Value TME engineering with clinical data. Weight clinical evidence over preclinical mechanism.

Apply appropriate timelines. Solid tumor CAR-T approval is likely years away. Account for extended development timelines and higher clinical failure rates.

The opportunity is proportional to the challenge. Solid tumors represent the majority of cancer incidence. Strategic acquirers who develop expertise in evaluating these programs position themselves to capture value when breakthroughs emerge.

Next in series: Beyond Autologous

Previous: CAR-T Generations: A Practical Guide

For advisory on cell therapy partnership strategy, contact Kerlann Advisory.