Mitigating Challenges In Solid Tumor Delivery

By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1

Last month, I attended PMWC 2026 in Santa Clara, and I had the good fortune to moderate the session, “CAR T Cell Therapies: Strategies in Mitigating Challenges in Solid Tumor Delivery.”  I was honored to share the stage with these distinguished experts:

• Carl June, M.D., Richard W. Vague Professor in Immunotherapy; Director, Center for Cellular Immunotherapies; Director, Parker Institute for Cancer Therapy at University of Pennsylvania Perelman School of Medicine
• Michel Sadelain, M.D., Ph.D., Director of the Columbia Initiative in Cell Engineering and Therapy (CICET), Columbia University, and
• David Barrett, M.D., Ph.D., VP of Cell Biology, Kite Pharma

We discussed the central challenge of adapting CAR T-cell therapy, which is highly successful in blood cancers, to solid tumors. Our conversation was structured around four key strategic areas: target selection, trafficking, overcoming the tumor microenvironment, and sustaining T-cell function. Across all four topics, a consistent theme emerged: while proof-of-concept successes are growing, solid tumors present layered biological barriers that require multifaceted and often combinatorial solutions.

Target Selection

We began with target selection, widely considered the foundational challenge. In hematologic cancers, CAR T-cell success has been driven by targets like CD19, which are largely restricted to malignant B cells. However, as Dr. Sadelain emphasized, solid tumor targets are “dirty;” they are often expressed on both tumor and essential normal tissues, raising safety concerns. This lack of tumor specificity complicates the therapeutic window and introduces risks of on-target, off-tumor toxicity. Additionally, tumor heterogeneity further undermines single-target strategies, as not all tumor cells express the same antigen, enabling escape mechanisms.

Drs. June and Barrett highlighted recent progress that suggests cautious optimism. Clinical data from neuroblastoma and gastric cancers demonstrate that CAR T-cells can achieve measurable responses in solid tumors, including results from randomized trials. However, these responses are modest and often lack durability. Dr. Barrett underscored the complexity of translating promising targets into viable therapies, noting that scientific enthusiasm must be tempered by safety, regulatory feasibility, and commercial considerations. Some targets may appear compelling but are deprioritized due to uncertain toxicity profiles or lack of predictive preclinical models. Ultimately, the field is revisiting previously discarded targets with improved technologies and better biological understanding.

Trafficking and Entry for T Cells

The second major challenge we discussed was trafficking or getting CAR T-cells into solid tumors. Unlike blood cancers, where T-cells naturally circulate through the bone marrow and lymphatic system, solid tumors actively exclude immune cells. Dr. Barrett described this as a fundamental shift; in hematologic malignancies, trafficking is essentially “free,” but in solid tumors it must be engineered. Strategies to address this include modifying CAR T cells to respond to tumor-specific chemokines, combining therapies with agents such as oncolytic viruses to attract immune cells, and delivering cells directly into tumor sites.

Dr. June provided concrete clinical insights from glioblastoma trials, where localized delivery via implanted reservoirs, combined with dual-targeting CARs, significantly improved response rates compared to earlier approaches. However, this success is not universal. In metastatic pancreatic cancer, even direct delivery of large numbers of CAR T-cells failed to generate meaningful responses, underscoring the variability between tumor types. Dr. Sadelain added that timing and route of delivery affect T-cell quality: cells that reach tumors quickly are more effective than those that arrive after prolonged circulation, suggesting that not just quantity but functional state at arrival is critical.

The panel also explored innovative approaches to enhance trafficking, including engineering bacteria or viruses to seed tumors and attract immune responses. While promising, these strategies introduce additional regulatory and logistical complexities, particularly around safety and transmissibility.

Inside the Immunosuppressive Tumor Microenvironment

The third focus area was the immunosuppressive tumor microenvironment, which inhibits CAR T-cell activity even when cells successfully infiltrate tumors. All three panelists agreed that there is no single dominant mechanism across all cancers, but recurring factors such as TGF-beta signaling and immune checkpoints such as PD-1 play central roles. One advantage of cell therapy, Dr. Sadelain noted, is the ability to genetically engineer T-cells to resist or even reprogram these suppressive signals.

Dr. Barrett emphasized the limitations of current preclinical models, particularly mouse systems, which often fail to predict human responses. As a result, much of the field’s progress relies on iterative clinical experimentation. Dr. June expanded on this by distinguishing between extrinsic barriers (such as the tumor microenvironment) and intrinsic T-cell limitations (such as exhaustion). He highlighted advances in gene editing and functional screening, including discoveries of genes that influence T-cell persistence and potency. However, with hundreds of potential genetic targets, prioritization remains a challenge.

A notable proposal from Dr. June was the introduction of phase zero clinical trials for cell therapies: small, exploratory human studies designed to rapidly identify optimal engineering strategies. He argued that such approaches could significantly accelerate progress compared to traditional preclinical pipelines, which are slow and often poorly predictive.

Sustainability of CAR T-Cell Functionality

The final major theme was sustaining CAR T-cell functionality over time. While persistence of cells has traditionally been viewed as important, Dr. Sadelain clarified that functional persistence, or continued activity rather than mere presence, is the critical factor. In some blood cancers, long-term remission occurs even after CAR T-cells become nearly undetectable, but solid tumors likely require more sustained engagement.

Several engineering strategies are being explored to address this, including cytokine armoring (e.g., IL-15 or IL-18 expression), gene edits to prevent exhaustion, and switch receptors that convert inhibitory signals into activating ones. Dr. June suggested that combinations of these approaches will likely be necessary. Dr. Barrett added that lessons from earlier CAR T successes, such as the importance of using less differentiated, “younger” T cells, remain relevant, though their applicability to solid tumors is still being tested.

In closing, the panelists resisted naming a single breakthrough area, emphasizing instead that progress will depend on integrating advances across all four domains. Dr. Sadelain pointed to the need for deeper exploration of novel tumor-specific targets, including unconventional antigens derived from glycosylation patterns or previously unrecognized genomic regions. Dr. June highlighted glioblastoma as a near-term opportunity due to its localized nature and lack of effective treatments, while Dr. Barrett emphasized the goal of engaging the broader immune system to generate a systemic, durable anti-tumor response.

Overall, our discussion reflected a field transitioning from early skepticism to cautious momentum. While significant scientific and clinical hurdles remain, the convergence of improved targeting, smarter engineering, and deeper biological insight is steadily bringing CAR T-cell therapy closer to meaningful impact in solid tumors.