Reprogramming T-Cell Access To Solid Tumors Through Improved Trafficking And Entry

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

Extending CAR T-cell success beyond hematologic malignancies requires more than identifying the right target; it requires getting engineered cells to the tumor in the first place. At PMWC 2026 in Santa Clara, I moderated a panel featuring industry luminaries, Dr. David Barrett, Dr. Carl June, and Dr. Michel Sadelain, who emphasized that trafficking and entry remain some of the most fundamental (and unresolved) barriers in solid tumor cell therapy.

In earlier coverage of PMWC 2026, I explored the first critical pillar of solid tumor CAR T strategy, target selection, along with a full session recap. This article turns to the next challenge from that discussion: how to improve trafficking and entry to enable CAR T-cells to reach and function within solid tumors.

When Natural Trafficking Advantages No Longer Apply in Solid Tumors

In hematologic cancers, trafficking is largely taken for granted. As Dr. Barrett explained, T-cells naturally circulate through the blood, bone marrow, and lymphoid tissues, precisely where leukemias and lymphomas reside. This biological alignment made early CAR T successes possible without needing to solve for delivery.

Solid tumors present the opposite scenario. Tumors such as pancreatic, ovarian, and metastatic lung cancers are often located in anatomically complex, poorly vascularized, or immunologically excluded environments. Even when some antigen presentation occurs in draining lymph nodes, it does not translate into meaningful T-cell infiltration at the tumor site.

This shift transforms trafficking from a passive advantage into an active engineering challenge.

Engineering T-Cells to Follow the Right Signals

One major strategy discussed is leveraging chemokine biology. Tumors secrete specific chemokines, but endogenous T-cells often fail to respond effectively. Engineering CAR T-cells to express matching chemokine receptors offers a way to tune them to tumor-derived signals.

However, this approach is not straightforward. Tumors actively evolve to suppress or misdirect immune trafficking signals. As Dr. Barrett noted, “the tumor has already figured out how to exclude the immune system,” meaning any solution must overcome an actively hostile environment, not just a passive barrier.

This has led to combination strategies, including:

• Pairing CAR T-cells with agents that modify tumor signaling
• Inducing tumors to express chemoattractants artificially
• Leveraging adjunct modalities to mobilize immune cells

Bypassing Trafficking Altogether with Local Delivery

An alternative approach is to circumvent trafficking entirely through regional or local delivery. Dr. June highlighted significant learnings from glioblastoma trials, where CAR T-cells were delivered directly into the tumor via implanted reservoirs.

The results were striking in that combining dual targeting with local delivery yielded response rates around 50% in early studies, far exceeding prior attempts with systemic infusion.

This reinforces two critical insights:

• Physical proximity matters: getting T-cells to the tumor site is itself therapeutic
• Delivery route can dramatically alter efficacy, not just distribution

However, this strategy is not universally effective. In pancreatic cancer, even direct infusion into tumor-draining regions failed to induce meaningful infiltration or inflammation. Biopsies revealed that tumors remained cold, underscoring that presence alone is insufficient without penetration and activation.

Timing and T-Cell Fitness

Dr. Sadelain introduced a more subtle but critical dimension: time-to-tumor entry affects T-cell quality.

Preclinical models showed that CAR T-cells delivered directly to tumors outperformed those that arrived days later via systemic circulation even when equal numbers ultimately reached the site. Delayed-arriving cells exhibited reduced functional capacity, potentially due to signaling fatigue or environmental conditioning during transit.

This suggests trafficking is not just about how many cells arrive, but when and in what state they arrive, adding another layer of complexity to delivery strategy design.

Reprogramming the Tumor Microenvironment

Given that many tumors actively exclude immune cells, another emerging strategy is to modify the tumor itself to allow entry.

Our panelists highlighted several approaches:

• Oncolytic viruses to infect tumors and trigger immune recruitment
• Engineered bacteria that preferentially localize to tumors and create inflammatory signals
• Agents that degrade stromal barriers or alter extracellular matrix composition

Dr. June described early clinical efforts combining CAR T-cells with oncolytic viruses. While still preliminary, these studies showed partial responses where CAR T-cells alone had failed, suggesting that priming the tumor environment may be essential for trafficking success.

However, these strategies introduce new challenges, particularly regulatory complexity and safety concerns associated with live or replicating agents.

The Barriers of Physical and Biological Exclusion

Even when T-cells reach the tumor vicinity, they often cannot penetrate it. Dense stromal structures, especially in tumors such as pancreatic cancer, create physical barriers composed of collagen and fibroblasts. These structures prevent both immune cells and therapeutics from entering.

This has led to exploration of:

• Anti-stromal targeting strategies (e.g., fibroblast activation protein)
• Matrix-degrading enzymes
• Combination therapies to open the tumor before CAR T infusion

The panel emphasized that trafficking and infiltration are distinct problems, solving one does not guarantee the other.

One Strategy or Many?

A key question raised was whether a single trafficking solution could address metastatic disease across organs. The consensus: unlikely.

Different tissues present unique microenvironments, vascular structures, and immunologic barriers. Brain tumors, liver metastases, and peritoneal disease each require distinct approaches. As a result, the field is likely moving toward organ-specific or context-dependent trafficking strategies rather than a universal solution.

Trafficking Will Require an Integrated Approach

Our discussion made clear that trafficking is no longer a secondary consideration; it is central to the success of solid tumor cell therapy. Progress will likely come from integrated approaches that combine:

• Cell engineering (chemokine receptors, fitness optimization)
• Delivery innovation (regional vs systemic)
• Microenvironment modulation (viruses, bacteria, stromal targeting)

Ultimately, solving trafficking may require treating it not as a single hurdle, but as a coordinated system problem that spans biology, engineering, and clinical strategy.