Adaeze Ekwe, PhD, MSc
Junior Associate Editor, ISCT Telegraft
Queensland University of Technology (QUT)
Australia
 
Joaquim Vives, PhD
Contributing Editor, ISCT Telegraft
Banc de Sang i Teixits (BST)
Spain

Topic Overview

Solid tumours have long resisted immunotherapy through a combination of antigenic heterogeneity, physical barriers, and immunosuppressive microenvironments¹. The failure mode of many early solid tumour immunotherapies is now well understood. When immune pressure is focused on a single antigen, cancer cells simply downregulate or lose that target, a process known as “antigen escape”. In highly heterogeneous tumours such as pancreatic ductal adenocarcinoma (PDAC), glioblastoma, and advanced gastrointestinal cancers, this evolutionary escape can occur rapidly, leading to transient responses followed by relapse^{1, 2}.

Multiantigen-targeted strategies have begun to shift this paradigm by directly addressing these vulnerabilities. Rather than relying on a single surface marker, these therapies target several tumour associated antigens (TAAs) at once, often chosen for their complementary expression patterns and biological importance to tumour survival. The simultaneous targeting of multiple TAAs reduces antigen escape, matches tumour heterogeneity and triggers “epitope spreading” where endogenous immunity expands beyond the original targets^{1, 2}.
Multiantigen-targeted T cell strategies—including tumour infiltrating lymphocytes (TILs), multi TAA–specific cytotoxic T cells, dual/multi target CAR T cells, and TCR based platforms— using both genetically engineered and non engineered cells are actively being tested across pancreatic cancer, glioblastoma, mesothelioma, melanoma, sarcoma, and lung cancer^2-6.
In this piece, we spotlight these therapies and real-world implications for several stakeholders.

Expert Perspectives

• Ann Leen, Professor, Baylor College of Medicine (USA): “Our experience with multiantigen targeted T cells demonstrates their safety, ability to infiltrate tumors and persist over the long term. In our recent PDAC trial we found that clinical outcomes correlated with peripheral expansion of the infused cells and treatment-emergent antigen spreading, highlighting the link between immunological fitness and patient benefit. Both the safety profile and clinical promise seen in an immunologically “cold” tumor such as PDAC paves the way for broader use of this modality at early disease stages. Furthermore, there is significant opportunity for additive/synergistic benefit by combining multiantigen targeted T cells with complimentary immunotherapies (e.g. checkpoint therapies, vaccines, etc) and/or standard-of-care (SOC) chemotherapy.”
  
  
• Dr. Petr Lesný, Institute of Haematology and Blood Transfusion (Czech Republic): “The concept of combinatorial or multi-antigen targeting represents a logical next step in the evolution of engineered cell therapies. By simultaneously addressing tumor heterogeneity and antigen escape, such strategies could significantly enhance the robustness of cellular immunotherapies. Nevertheless, first impactful clinical applications of the combinatorial approach will probably emerge in hematologic malignancies, where the target cells are more accessible, antigen expression patterns are better characterized, and therapeutic monitoring is straightforward. In solid tumors, the principal challenge remains the non-permissive tumor microenvironment, which limits immune-cell infiltration, persistence, and functional activity. Combinatorial antigen recognition alone may be ineffective in overcoming these barriers. For this reason, future therapeutic platforms will probably need to utilize not only the combinatorial approach, but also integrate additional cellular engineering strategies—such as receptor knockouts, checkpoint-resistant designs, or the genetic and electroporation-based modification of known tumor-infiltrating lymphocytes—to enhance trafficking, resistance to immunosuppression, and sustained anti-tumor activity.”
  
  
• Siok Tey, Professor, QIMR Berghofer Medical Research Institute (Australia): “Scientists and clinicians have long known that targeting more than one antigen is desirable and often necessary in cancer immunotherapy but addressing the ‘how’ or ‘how best’ takes time. We now have a series of clinical trials that demonstrate not only the feasibility but also the clinical efficacy of multi-antigen targeting, for both surface and intracellular antigens. Perhaps one of the most clinically significant aspects of the current generation of T cell therapies directed at intracellular antigens is the use of overlapping peptides rather than selected Human Leukocyte Antigen (HLA)-restricted peptides or T cell receptor (TCR) transgenics. This means that these therapies are no longer restricted to individuals who express specific HLA alleles (e.g. HLA-A2), thus ensuring broad and equitable applicability across population groups.  The choice of antigen combinations will undoubtedly become more refined with the rapid expansion in single cell dataset. As for the vehicles, we now have an ever expanding smorgasbord of cell therapy and non-cell therapy options: autologous T cells versus vaccines for intracellular antigens; and CAR T cells (autologous, allogeneic and in vivo CAR) versus bispecific antibodies for surface antigens.  I think efficacy will likely be the key determinant of their broader uptake  - the successful roll out of CAR T cell therapy has demonstrated that manufacturing and delivery challenges can be met for if there is sufficient will and incentive.”
  
  
• Dr. Adomas Bukauskas, Vilnius University Hospital Santaros Klinikos (Lithuania): “CAR-T cell therapy has transformed the management of several hematological malignancies; dual-target and tri-specific CAR designs have been developed and evaluated to improve efficacy and mitigate antigen escape. In solid tumors, however, CAR-T cell efficacy is constrained by limited tumor infiltration, suboptimal expansion and persistence, relapse associated with antigen downregulation or heterogeneity, and an immunosuppressive tumor microenvironment. Overcoming these challenges will require engineering strategies that expand target coverage and enhance intratumoral trafficking, persistence, and sustained activity.”

Insights Across the Ecosystem

For Patients

• Improved safety and quality of life: Standard immunotherapies often come with the risk of high-grade cytokine release syndrome (CRS) and neurotoxicity, but this multiantigen-targeting approach has been shown to be exceptionally well-tolerated with moderate to no CRS. In a recent phase 1/2 trial using autologous multiantigen-targeted T cell for PDAC, only one treatment-related serious adverse event was reported across 140 infusions from the 37-patient cohort⁶. 
• Durable remission: Multiantigen-targeted T cells often demonstrate long-term persistence post infusion and evidence of epitope spreading which is now recognized as a key correlate of durable responses across immunotherapies, including adoptive T cell therapies and checkpoint inhibitors.
• Earlier access: With the standard shifting towards multiantigen-targeted therapies after chemotherapy, patients receive therapy when tumour burden is lower rather than only at end-stage.

For Clinicians and Researchers

• From target selection to system engineering: With the standard shifting towards multiantigen-targeted therapies after chemotherapy, patients receive therapy when tumour burden is lower rather than only at end-stage.
• Adaptive clinical trials: Increasingly, durable clinical benefit appears to correlate less with peak tumour shrinkage and more with immune persistence, antigen breadth, and endogenous immune engagement. Disease control rate and durability become as important as response rate removing rigid single-endpoint designs, and trials at early-stage of disease scientifically justified.

For Developers and Industry

• Less engineering and more biological simplicity: Most multiantigen-targeting therapies emphasize preserving natural T-cell biology as opposed to more genetic edits and synthetic signalling. Thus, success may depend less on maximal engineering and more on biologically informed simplicity. This has a huge commercial impact, strengthening the business case for solid tumour cell therapies beyond niche, orphan indications.
• Manufacturing and scalability: Many multiantigen-targeting therapy platforms, particularly non engineered or lightly engineered approaches, may be more scalable than traditional CAR T therapies. By avoiding viral vectors, the manufacturing process is potentially more streamlined and scalable. Additionally, this could result in a lower-cost entry point for treating common solid tumours increasing global deployment.

For Regulators, Payers and Policy Makers

• Regulatory Frameworks: The accelerated FDA approvals of Lifileucel (TIL therapy) and Afamitresgene autoleucel (TCR T) for melanoma and synovial sarcoma respectively based on single-arm data, duration of response and immune persistence signal a broader regulatory acceptance of antigen diversity in solid tumour immunotherapy. Additionally, the lower risk of toxicity and controlled manufacturing variability in the absence of viral vectors (for non-engineered platforms) align better with regulatory risk tolerance.
• Treatment consolidation: With evidence from multiple trials increasingly supporting integration into standard treatment sequences, policy makers will need to update treatment guidelines to reflect earlier-line cellular immunotherapy rather than last resort.
• Better economics: Traditional CAR-T therapies are dominated by indirect costs from ICU admissions, management of CRS and prolonged hospital stays. Multiantigen targeting T cell therapies particularly non-engineered or TCR-based platforms have shown lower rates of high-grade toxicity, less ICU utilization and outpatient administration in some trials. This has implications for potentially lower cost of care.
• Improved equity and global access: Lower toxicity and reduced ICU demand will enable decentralization beyond elite CAR-T centres and improve access in public systems and regional hospitals. Multi-antigen, non-engineered platforms avoid viral vector supply constraints, offer simpler manufacturing pathways and lower per-patient infrastructure burden.

Global Viewpoint

Current clinical and translational evidence strongly suggests that multi‑antigen targeting is becoming a defining pillar of effective solid‑tumour immunotherapy, precisely because it addresses the core biological barriers that have limited prior approaches. High income regions such as the US, EU, and Australia are already integrating cellular immunotherapy infrastructure, but historically high costs, ICU level toxicity, and manufacturing bottlenecks have limited broader access. Multiantigen-targeting strategies, especially non engineered or lightly engineered platforms, offer a potential inflection point. By reducing reliance on viral vectors, lowering severe toxicity rates, and enabling outpatient or short stay administration, these approaches may be more scalable and adaptable to public health systems, including those in middle income countries. Countries across Asia Pacific, Europe, and emerging markets are investing heavily in cell therapy infrastructure, and multiantigen-targeting strategies may offer a more practical path to equitable deployment than earlier CAR-T models. China’s rapid progress with advanced solid tumour CAR T programs (e.g., Claudin18.2 targeted therapies) further underscores the global race to operationalize these platforms beyond niche indications.

What to Watch

• The Rise of "Logic Gating": Expect more clinical data on AND/OR gates. Industry leaders like Autolus (targeting CD19/22) and Mustang Bio (CD20/19) are proving that "OR-gates" can prevent relapse, while "AND-gates" are currently the "holy grail" for safety in solid tumours.
• The Engineering vs. Simplicity Debate: Watch the competition between highly engineered "armored" CAR-Ts (which carry extra cytokine "payloads" like IL-15) and "non-engineered" multi-TAA T-cells. The winner will likely be determined by who can achieve long-term persistence with the lowest manufacturing footprint.
• Decentralized Manufacturing: With the shift away from viral vectors in some multi-antigen platforms, watch for the emergence of "Point-of-Care" (POC) manufacturing models. This could allow regional Blood, Cell and Tissue Centres (BTCs) to produce multi-antigen T-cells locally, fundamentally changing the reimbursement and access landscape for ATMPs.

references

1. Escobar, G., T.R. Berger, and M.V. Maus, CAR-T cells in solid tumors: Challenges and breakthroughs. Cell Reports Medicine, 2025. 6(11).
2. Lu, Y. and F. Zhao, Strategies to overcome tumour relapse caused by antigen escape after CAR T therapy. Molecular Cancer, 2025. 24(1): p. 126.
3. Li, W., et al., Emerging advances in CAR-T therapy for solid tumors: latest clinical trial updates from 2025 ASCO annual meeting. Journal of Hematology & Oncology, 2025. 18(1): p. 104.
4. Bagley, S.J., et al., Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nature Medicine, 2024. 30(5): p. 1320-1329.
5. Bagley, S.J., et al., Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial. Nature Medicine, 2025. 31(8): p. 2778-2787.
6. Musher, B.L., et al., Autologous multiantigen-targeted T cell therapy for pancreatic cancer: a phase 1/2 trial. Nature Medicine, 2026. 32(1): p. 258-269.