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Rajdeep Das, MD, PhD, FIBMS
Member, ISCT Lab Practices Committee
University Hospitals Cleveland Medical Center
United States

Karen E. Martin, PhD
Department of Biomedial Engineering
Tufts University
United States

Medhat Askar, MD, PhD, MSHPE, FRCPath
Member, ISCT Lab Practices Committee
Texas A&M College of Medicine
United States

Consider this scenario: a patient with relapsed, refractory disease has exhausted standard options. A promising allogeneic CAR-T trial has opened nearby. The product is engineered, potent, and available now. No apheresis delay. No manufacturing wait.

Then, the HLA typing comes back. The patient does not carry HLA-A*02:01 — the allele required for trial eligibility. They are out. Not because of disease biology, not because of performance status, but because of two letters and four digits.

We have made progress against the manufacturing bottleneck that constrained autologous products and, in doing so, exposed another bottleneck embedded in the patient's genome.

The New Bottleneck

Allogeneic CAR-T, CAR-NK, TCR-engineered lymphocytes, and iPSC-derived effectors are reshaping cellular therapy. Yet many current platforms rely on narrow HLA restrictions, often HLA-A*02:01, to simplify early development. That is an understandable engineering decision — and an exclusion criterion.

Because HLA allele frequencies vary across ancestry groups, allele-restricted designs do not exclude patients at random. Even for eligible patients, HLA mismatch can drive host-mediated rejection, undermining persistence and durability.

For readers who are in the field of cell therapy, this is a laboratory practices problem.

Four Ways to Widen the Gate

So how do we expand access without sacrificing the platforms we have worked so hard to build? A recent framework published in Frontiers in Immunology organizes mitigation strategies into four complementary domains.

1. Population-Informed Matching

If we cannot match everyone, we can match strategically. Haplotype-homozygous donors, including those used for iPSC banks, can provide broad coverage with relatively few cell lines. Cord blood units, already HLA-typed and more mismatch-tolerant, may add another layer. For HLA laboratories, allele and haplotype frequency analysis is becoming translational infrastructure.

2. HLA Engineering

Genome-editing strategies, most commonly targeting B2M (Beta-2-Microglobulin) or CIITA (Class II Transactivator), can significantly reduce classical HLA class I and II expression, thereby preventing T cell-mediated rejection of allogeneic cell products. To mitigate the subsequent risk of NK-cell activation, these edits are often paired with the expression of minimally polymorphic molecules such as HLA-E or HLA-G. Additionally, the TRAC (T-cell receptor alpha constant) gene can be knocked out in T cell products to eliminate the endogenous T cell receptor and prevent graft-versus-host disease (GvHD). The goal is a more universal donor product, but tradeoffs remain: NK susceptibility, altered immune surveillance, and unresolved long-term oncogenic and infectious risks.

3. Clinical Modulation

Not every barrier must be solved at the product level. Current adoptive cell therapy products, both autologous and allogeneic, rely on lymphodepletion regimens, such as fludarabine and cyclophosphamide, to maximize engraftment, efficacy, and long-term durability. Additionally, in the allogeneic context, lymphodepletion creates a critical therapeutic window by temporarily depleting host alloreactive cells. This allows allogeneic products to exert their anti-tumor effects even when donor and recipient HLAs are not matched. Optimizing short-course immunosuppression, lymphodepletion protocols, and strategic infusion scheduling, combined with partial HLA matching, could significantly widen this therapeutic window. The same product may perform differently depending on immunologic context.

4. Immunologic Risk Stratification

Donor-specific antibodies (DSA) have long predicted graft failure in solid organ transplantation. Their role in allogeneic cellular immunotherapy is newer but increasingly relevant, particularly for repeat-dosing strategies and applications requiring prolonged cellular persistence. This becomes especially important as adoptive cell therapy use expands beyond B-cell malignancies. In CD19-targeted CAR T-cell therapy, the treatment eliminates both malignant and healthy B-cell populations, effectively depleting the source of anti-product antibodies. Treatments for other indications, however, would encounter an intact humoral immune system. DSA screening is strategy-agnostic — it applies regardless of which upstream approach a product uses, and transplant medicine already offers decades of practical guidance worth borrowing.

Why This Lands in the Laboratory

Histocompatibility and immunogenetics laboratories are the connective tissue holding this framework together. High-resolution HLA typing, haplotype analysis, DSA detection, and functional alloimmune assessment inform platform design, donor selection, eligibility criteria, and risk stratification.

Three practical implications stand out. First, get involved early: immunogenetic input during target selection, donor-source planning, and protocol design can prevent surprises at infusion. Second, expect standardized reporting: HLA assumptions, coverage estimates, and mitigation strategies will likely face scrutiny. Third, talk across silos: manufacturing, clinical, and HLA teams need to align before protocols are finalized.

The Shift Worth Making

The key idea is not any single technique. It is the reframing.

HLA incompatibility has too often been treated as a downstream nuisance — something to manage after the product is designed, the trial is written, or the patient is enrolled, which seems backwards. HLA coverage is a controllable design variable. It can be modeled, engineered, stratified, and monitored. It belongs at the top of the development whiteboard, not in the footnotes.

The scalable future of cellular immunotherapy will be shaped by those who build the most potent product that the most patients can actually receive. That is a laboratory problem as much as a clinical problem, which our community is uniquely equipped to solve.

Adapted from: Das R, Askar M. HLA incompatibility mitigation strategies in off-the-shelf cancer immunotherapies: clinical implications and a practical framework for strategy selection and combination. Front Immunol 17:1803331 (2026).