Cell Therapy’s Lot in Solid Tumors: Challenges and Opportunities
Several experts weighed in on the various strategies being explored to tackle solid tumors with cell therapy, expressing optimism despite the plethora of obstacles that remain.
Over the past 5 to 10 years, chimeric antigen receptor T-cell (CAR-T) therapy has firmly established itself as an effective treatment modality for blood cancers, with several products having been approved by the FDA for such indications, such as Janssen and Legend Biotech’s ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti) and Bristol Myers Squibb (BMS) and 2seventy bio’s idecabtagene vicleucel (ide-cel; marketed as Abecma). In light of this success, it only seems natural for investigators to seek to apply the same technology to solid tumor indications. After all, around 90% of cancers found in adult patients are varieties of solid tumors, and these malignancies can originate in myriad organs throughout the body.1,2
Unfortunately, attempts to apply existing CAR-T approaches that proved effective in blood cancers to solid tumor indications has raised a number of difficulties related to key aspects of solid tumor biology.3 It has therefore become clear that a simple plug-and-play transfer of the technology is thoroughly insufficient. Indeed, a modified approach to CAR-T and/or other engineered cell therapy approaches will be necessary to make the modality of cell therapy able to provide clinically meaningful benefit for solid tumors.
This issue has been known for several years, and a number of biotech companies and academic institutions are already trying their hand at a variety of methods meant to overcome the barriers in place. Although some promising studies have been carried out, the task is still very much a work in progress, and it remains to be seen which, if any, of the approaches currently under evaluation will eventually become part of standard clinical practice. With the aim of getting a cross-section of the current state of progress in the field, CGTLive® reached out to several experts to get their insight into several of the notable approaches currently being assessed.
Using Armored CAR T-Cells to Tackle Solid Tumors
“Over the brief 20-year span that I've been doing this work, I think we philosophically kind of changed how we look at [CAR T-cells as cytotoxic agents], and we realized that the CAR T-cell may be more of a spark rather than the actual explosion."
One noteworthy approach currently being applied is the concept of “armored CAR T-cells.” There are CAR-T products that have additional genetic modifications beyond the typical CAR modification itself that are intended to combat cancer cells in additional ways. The additional genetic modification can be almost anything. For example, a proinflammatory cytokine potentially capable of modulating the tumor microenvironment could potentially help to further elicit a patient's own endogenous immune response to aid in attacking the tumor.
Renier Brentjens, MD, PhD, the chair of the department of medicine and the deputy director at Roswell Park Comprehensive Cancer Center, spoke to CGTLive about how armored CAR T-cells may help bridge the gap necessary to make CAR-T effective in solid tumors. Brentjens pointed out that unlike blood cancers, solid tumors are more complex, and often surrounded by nontumor cells that block immune responses. He explained that armored CAR T-cells can reshape this environment and trigger the body’s natural immune system to help attack the cancer.
“Over the brief 20-year span that I've been doing this work, I think we philosophically kind of changed how we look at [CAR T-cells as cytotoxic agents], and we realized that the CAR T-cell may be more of a spark rather than the actual explosion," Brentjens told CGTLive. "It's the spark that sets off a downstream effect where an immune system that is actually quite reasonably sophisticated in recognizing cancer cells can overcome the defenses that cancer cells create around themselves to stop cell therapies from working.”
Furthermore, he emphasized that in solid tumors, armored CAR T-cells may help address antigen escape. He noted that this is typically an even greater challenge for solid tumors than it is in blood cancers.
Addressing T-Cell Exhaustion
“...Overcoming this obstacle, I think, is going to be an important piece of designing and engineering T-cell engineered T-cell therapeutics that can actually cure patients.”
Despite the successes seen so far with CAR-T therapies in clinical trials and in the real-world setting for blood cancers, even in these hematologic malignancies, the modality continues to have a number of limitations. Among these are the phenomena of T-cell exhaustion, in which the CAR T-cells become less functional over time, and the limited persistence of CAR T-cells. It is thought that these phenomena may reduce the efficacy and durability of responses from CAR-T therapy, potentially leading patients to relapse.4 Although means of addressing these limitations are certainly of interest for improving the efficacy of CAR-T in blood cancer indications, tackling these same shortcomings may also give a much-needed boost to the efficacy of attempts to bring CAR-T to solid tumors.
On both these counts, methods to overcome T-cell exhaustion and enhance the persistence of CAR T-cells are a major area of focus for ongoing CAR-T research in the lab of Evan Weber, PhD, an assistant professor of pediatrics at Children's Hospital of Philadelphia, and his colleagues. In an interview with CGTLive, Weber discussed the importance of these phenomena in the larger puzzle of making CAR-T effective in solid tumors, positing that addressing them may be a critical piece to enabling the therapies to be curative.
“Overcoming T-cell exhaustion, which is exactly what it sounds like—it's a process whereby T-cells lose the ability to promote antitumor function both in liquid and solid tumors—overcoming this obstacle, I think, is going to be an important piece of designing and engineering T-cell engineered T-cell therapeutics that can actually cure patients," Weber told CGTLive.
Weber also shared his thoughts on the broader array of cell therapy approaches currently being explored to treat solid tumors, such as tumor-infiltrating lymphocyte (TIL) therapies and T-cell receptor (TCR) T-cell therapy, and how improved CAR-T therapies may fit into that landscape. He suggested that different approaches may end up carving out different niches where they are shown to be most effective.
Targets, Logic-Gating, and Logistics
“For example, mesothelin-targeted CAR-T has been a very potent CAR T-cell. It does kill tumor cells that express mesothelin—mesothelioma, adenocarcinoma of the ovary, adenocarcinoma of the lung—and yet, it also attacks the peritoneum, it attacks the pleura, and has been essentially a nonstarter in phase 1 trials until recently.”
In hematologic malignancies, CD19 and BCMA have proven to be efficacious targets for CARs. These antigens exist in sufficient quantity on hematologic cancer cells and in low enough quantities in healthy cells to provide a favorable balance with regard to on-target cell killing. The application of CAR-T to solid tumors, however, requires identifying new antigen targets depending on the solid cancer type being addressed.5,6 Unfortunately, many antigens that could be potential candidates as targets for solid tumor cell therapies, such as mesothelin, come with higher levels of on-target, off-tumor toxicity than is seen with the targeting of CD19 and BCMA in blood cancers.
One approach aimed at getting around this conundrum is logic-gating.6,7 Unlike the CAR-T therapies that have been FDA-approved for use against hematologic malignancies that simply target and kill cells expressing a known tumor antigen, logic-gated CAR T-cells allow for more selective cell killing. Depending on the particular construct, they are designed to only activate in both the presence of a target antigen and the absence of a different marker expected to only appear on healthy cells (on-off switch construct) or to only activate in the presence of 2 target antigens (on-on switch construct).5
In an interview with CGTLive, Ben Creelan, MD, a medical oncologist at Moffitt Cancer Center who specializes in oncology cell therapy research, discussed how logic-gating may help CAR-T achieve a more favorable balance of efficacy and safety in solid tumors by reducing off-tumor on-target toxicity. Creelan additionally spoke about the search for ideal antigen targets for solid tumor therapies in general, and in the course of the discussion touched on a number of recent relevant presentations given at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 30 to June 3, in Chicago, Illinois. He highlighted the potential of GPC3 as a target for a range of solid tumor types because it is found to be expressed on most squamous tumors. Other antigens he emphasized were potentially important targets included Claudin 6 and Claudin-18.
Creelan also noted the importance of logistics in making cell therapy a more viable option for solid tumors. In particular, he pointed out the potential benefits of allogeneic and in vivo approaches to manufacturing cell therapy for solid tumors. Allogeneic cell therapy could allow for faster time to treatment and in vivo CAR-T therapy could remove the need for aphaeresis and cut down costs.
The Big Picture
On the whole, there are myriad methods to making cell therapy a safe and effective treatment modality for a range solid tumors that are currently in the works. Although it may be tempting to debate which upcoming approach is most likely to be a game-changer, or which treating physicians ought to be most optimistic about, the reality may be that a combination of the aforementioned approaches (and potentially yet untested others as well) may end up needing to come together for cell therapy to be viable in cancers beyond hematologic malignancies and a handful of other indications. Indeed, Weber shared his view on this during the course of his discussion with CGTLive.
“One of the questions we receive typically, when we present our work publicly, is whether the specific manipulations or approaches that we're developing and engineering in our lab are the best ones out there,” Weber said. “Basically, how do you choose what manipulation to use for a given T-cell therapeutic? I think many of us in the field have, for a long time, had a tendency to claim that our approaches are broadly applicable and could be used to enhance CAR T-cells for solid tumors or liquid tumors or to equally enhance TCR-engineered T-cells and CAR T-cells—but much like my previous answer around different T-cell modalities and how they fit into the therapeutic landscape, I think that these manipulations around enhancing T-cell potency will also be context-specific.
"For example, armoring techniques for chemokines or cytokines may be appropriate for certain solid tumors and not others, just as transcription factor engineering approaches or other synthetic biology approaches may have context-specific use. I hope that as a field, we evolve our preclinical pipelines to tease some of that context-specificity out before the clinical stage.”
