Beyond Autologous

Building a Multi-Modal Cell Therapy Portfolio

Article 8 of 10 in a series on cell therapy partnership strategy.

Autologous CAR-T dominates the current commercial landscape, but it won't dominate the future. The inherent limitations of patient-derived manufacturing—cost, logistics, production variability, and access constraints—have driven investment into alternative modalities that promise to democratize cell therapy.

For strategic acquirers, the question is no longer whether to engage with emerging cell therapy modalities, but how to build a portfolio that captures upside across platforms while managing development risk.

Allogeneic CAR-T: The Scalability Promise

Allogeneic ("off-the-shelf") CAR-T uses donor T-cells rather than patient cells, enabling batch manufacturing from a single healthy donor. The theoretical advantages are substantial: immediate availability, standardized product quality, lower manufacturing cost per dose, and the potential for redosing.

The technical challenges are equally substantial. Donor T-cells risk graft-versus-host disease (GvHD) and are rapidly eliminated by the patient's immune system. Solving these problems requires genetic engineering to remove the endogenous T-cell receptor and eliminate recognition markers.

Clinical results show both promise and limitation. Allogeneic CAR-T can produce responses—proof of concept is established. But response durability has lagged autologous products.

Strategic assessment: Allogeneic remains a significant option if persistence challenges can be solved. The thesis depends on whether current engineering approaches will achieve autologous-equivalent durability.

CAR-NK: Different Biology, Different Profile

Natural killer (NK) cells offer an alternative effector cell platform with distinct biological properties. NK cells don't cause GvHD from allogeneic sources, and can be manufactured at unprecedented scale from cell lines or cord blood.

The safety profile differs meaningfully from CAR-T. NK cells don't typically cause cytokine release syndrome (CRS) or neurotoxicity at the rates seen with CAR-T. This enables outpatient administration and potentially broader treatment center access.

Manufacturing advantages are substantial. NK cell lines can be expanded industrially—some platforms achieve production scales of tens of billions of cells per batch, compared to patient-specific manufacturing for autologous CAR-T.

"NK cells don't typically cause CRS or neurotoxicity at CAR-T rates. This safety profile enables treatment settings that CAR-T cannot access."

Strategic assessment: CAR-NK may be the near-term winner for off-the-shelf cell therapy. The safety profile enables broader access, manufacturing scale enables cost-effective production, and clinical activity is demonstrated.

In Vivo CAR: Engineering Without Cell Manufacturing

The most disruptive potential modality eliminates cell manufacturing entirely. In vivo CAR approaches deliver genetic cargo—via lipid nanoparticles, viral vectors, or other delivery systems—that engineers the patient's own cells into CAR-expressing effectors without apheresis or ex vivo production.

The theoretical advantages are transformative: inject a product, create CAR-T cells in situ. No manufacturing facilities, no patient-specific production, no vein-to-vein time. The cost structure would approach small molecule or antibody economics.

Technical challenges remain substantial. Delivery efficiency is lower than ex vivo transduction. Durability is unproven. Clinical trials are beginning; data will emerge over the next 2-3 years.

Strategic assessment: In vivo CAR is the highest-risk, highest-reward modality. If it works with durable effect, it obsoletes much of the current cell therapy manufacturing infrastructure.

Portfolio Construction Framework

Given uncertainty about which modalities will ultimately succeed:

Core position: Autologous with rapid manufacturing. Autologous CAR-T works. Rapid manufacturing platforms address access limitations while preserving efficacy advantages. This should be the portfolio anchor.

Near-term diversification: CAR-NK. NK platforms offer the best near-term alternative profile—off-the-shelf availability, favorable safety, demonstrated activity.

Option position: Allogeneic CAR-T. Maintain exposure, but size positions to account for substantial clinical risk.

Long-term option: In vivo platforms. Include option-like exposure, recognizing that clinical validation is 3-5 years away.

The Multi-Modal Future

The cell therapy field is evolving from single-modality to multi-modal. Different modalities will likely win in different contexts. Autologous may remain optimal for curative-intent therapy. Allogeneic or NK may win for maintenance settings. In vivo may capture indications where cost prevents current cell therapy access.

The acquirers who succeed will be those who recognize that betting on a single modality is betting against optionality.

Next in series: Deal Architectures from Landmark Partnerships

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