Everyone loves a dark horse story.

Biotech, however, is one of the hardest arenas for spotting these overlooked contenders.

Because therapeutic development is so capital-intensive, investors must make massive commitments years before pivotal clinical trials occur, long before it’s clear which technology will prevail.

Within the cell therapy space specifically, investors are tracking a crucial question: which cell type will win the race to treat solid tumors?

For a while, the answer has seemed obvious. Ever since 2003, when the first CAR-T cells  were developed to find and destroy blood cancer cells, T-cells have been the darling of engineered cell therapies. By 2010, CAR-T cells had made their way to the clinic with resounding success. To date, seven CAR-T cell therapies have been approved by the FDA, with hundreds more in clinical development.

Yet, despite their success against blood cancers, CAR-T cell therapies have struggled to achieve similar efficacy in solid tumors, which account for over 90% of all cancer diagnoses.

Countless strategies are currently being pursued to bring CAR-T cells to the solid tumor market. But their struggle has also opened the door for other immune cell types to enter the race.

Some founders and investors have chosen to place their bets on T cell subsets or NK cells to carry out anti-tumor effects. But another family of immune cells—myeloid cells—have emerged as a possible contender.

Are myeloid cells the dark horse of cell therapy?

Myeloid cells, which include monocytes and the macrophages they develop into, are important immune cells with the unique ability to engulf biological threats in a process called ‘phagocytosis’.

In the current age of cell engineering, macrophages and monocytes can now be engineered to express a chimeric antigen receptor, or “CAR” protein, on their surface. Like CAR-T cells, CAR-Ms recognize and bind to cancer cells, triggering their destruction. But unlike CAR-T cells, which kill tumor cells by secreting cell-perforating molecules, CAR-M killing is thought to largely be mediated by phagocytosis of cancer cells.

Beyond their phagocytic capabilities, myeloid cells may have a home-field advantage in the solid tumor race. Unlike T cells, which often struggle to infiltrate tumors and can become exhausted in the immunosuppressive tumor environment, macrophages are already present within tumors and are adapted to survive in such harsh, low-oxygen conditions. When engineered correctly, they may also reshape the tumor microenvironment by secreting molecules that recruit and activate other immune cells—potentially orchestrating a broader anti-tumor immune response.

These powerful capabilities make engineering myeloid cells to target specific cancer cells an attractive strategy for tackling solid tumors.

Here, we investigate how CAR-Ms have so far fought to enter the race for solid tumor treatment, and what the future might look like for this potential dark horse cell type.

CAR-M’s growing momentum

How can we gauge momentum behind engineered myeloid cells? The magnitude of a therapeutic opportunity can often be reflected in the magnitude of academic interest.

Figure 1. The number of papers published between 2000 and 2025 on either engineered T cells (grey) or engineered macrophages (purple) (left). The number of papers published between January  June from 2022 to 2026 (right).

Unsurprisingly, since T cells were first engineered for therapeutic application, peer-reviewed papers published on the topic have skyrocketed (Figure 1 – left). In 2025 alone, 1,623 papers were published on T cell engineering. This dwarfs the 44 papers dedicated to engineering macrophages and monocytes, in the same year.

Yet zooming in on the last four years reveals something intriguing: myeloid cell engineering publications have risen sharply (Figure 1 – right), signaling growing interest in these cells as a cell therapy vehicle.

Indeed, nearly half of the publications so far in 2026 on macrophage/monocyte engineering involve expressing a CAR on these cells to trigger phagocytosis of solid tumor cells.

If myeloid cells are so promising, one might ask why their development lags so far behind their T cell counterparts? The timeline of discovery makes this especially puzzling, since macrophages were first observed in 1882, nearly an entire century before T cells were discovered in 1961.

This delay isn’t due to scientific skepticism—researchers have long understood the therapeutic potential of myeloid cells. Rather more likely, the bottleneck is technical: myeloid cells are notoriously resistant to foreign gene expression using conventional engineering approaches.

Figure 2. Timeline of discoveries on the journey to CAR T-cells and CAR-Ms as therapeutics. 

Since viral gene delivery methods came online in the 1990s, scientists have attempted to stably insert transgenes into myeloid cells with limited success. By contrast, T cells readily accept transgenes, including CAR expression vectors.

Luckily for the myeloid cell aficionados, the prospects of engineering them improved significantly in 2011, when a method to efficiently express transgenes in myeloid cells was published.

Though the first CAR-M prototype was generated in 2006, the recent ability to efficiently express transgenes in these cells has likely fueled the growing interest in using them as therapeutics.

The recent surge in macrophage and monocyte engineering studies follows a landmark study published in 2020 out of Dr. Saar Gill’s lab at the University of Pennsylvania. Leveraging insights from the 2011 transgene delivery method, Gill’s group demonstrated the ability of CAR-Ms to phagocytose cancer cells, both on a dish and in a mouse model of ovarian cancer. They also showed that CAR-Ms could reshape the solid tumor environment, stimulating a response from other immune cell types against the tumor in addition to their own targeted activity. This study—now cited nearly 1,600 times—has become the foundation for ongoing CAR-M development.

Carisma: the clinical trailblazer

As many know, publishing an academic paper is a far cry from clinical translation. It took nearly two decades to go from engineering T cells in a dish to the first infusion of CAR-T cell product into a patient.

Fortunately for myeloid cell engineering, T cells served as the guinea pigs for engineered cell therapies. The hard-won lessons—manufacturing challenges, safety hurdles, and regulatory pathways—were largely established during CAR-T cell development, paving a faster route to the clinic for myeloid cells.

This groundwork likely emboldened Carisma Therapeutics to advance CAR-Ms from preclinical studies to human trials. Founded by Dr. Michael Klichinsky and Dr. Saar Gill—the first and last authors of the 2020 landmark CAR-M paper—Carisma launched with a $53 million Series A to bring CAR-M therapies to patients with solid tumors.

The idea was simple: CAR-T, but in macrophages, following an analogous process: extract monocytes from the blood, differentiate them into macrophages, engineer them to express a CAR protein, and infuse them back into the patient.

Before continuing with the story of Carisma, it’s worth mentioning two spoilers: First, Carisma went on to complete a Phase I clinical trial, debuting the first-ever engineered macrophage therapy in 2021. Second, the company eventually ran out of funding, closing its doors in 2025.

Though Carisma’s vision of solving the solid tumor problem with engineered macrophages may not have come to fruition, they pioneered multiple firsts and learned critical lessons in the process. Both the successes and the challenges that this trailblazing company encountered are worth examining.

The early days of Carisma can be separated into two main efforts: driving the foundational CAR-M product forward and tackling the manufacturing problem.

Toward the first goal, Carisma built a preclinical foundation targeting HER2-positive cancers. They armed macrophages with a HER2-targeting CAR, hoping these cells could infiltrate tumors, kill cancer cells, and remodel the tumor microenvironment into one teeming with immune cells actively attacking the cancer.

At the same time, a hot topic in cell therapy was (and still is) the enormous cost and time burden associated with manufacturing engineered immune cells.

Acknowledging the benefits that accelerated manufacturing could bring to CAR-Ms, Carisma established several parallel efforts. Two are most notable: First, Carisma tested CAR expression in monocytes, creating CAR-Monos, which reduced the manufacturing time from one week to just one day. Second, they partnered with Moderna, receiving a $45 million upfront payment to adapt the biotech giant’s mRNA-encapsulating lipid nanoparticles (LNPs) for in vivo CAR-monocyte engineering.

Both these cost- and time-saving strategies were developed enough to generate meaningful preclinical data in multiple different solid tumor models.

Yet, despite these efforts to bring CAR-Monos and in vivo engineering into their clinical pipeline, it was the original ex vivo CAR-macrophage asset (CT-0508) that reached patients first.

In 2021, the first-ever engineered macrophage therapy was administered to a patient. Over the course of the Phase I clinical trial, fourteen patients with metastatic HER2-overexpressing solid tumors were treated with a HER2-targeting CAR-M product.

• The good? The treatment was safe. No neurotoxicity was reported, and only low-grade cytokine release syndrome was seen—two nasty side effects commonly associated with CAR-T cell therapy.
• The bad? CAR-Ms did not lead to tumor regression. The best overall response was stable disease, falling well short of the partial or complete responses needed to advance the therapy. Enrollment of new patients was subsequently suspended.

Though these clinical results were not ideal, Carisma carried on, continuing to make progress in generating CAR-Monos and engineering monocytes in vivo using Moderna’s LNP technology. In 2024, they even initiated a second Phase I trial for their lead CAR-Mono candidate (CT-0525), also targeting HER2-overexpressing solid tumors. However, these developments proved insufficient to save the company from buckling.

In 2025, Carisma implemented severe cost-cutting measures and ceased all research and development operations.Moderna terminated its collaboration agreement, and ultimately, Carisma reduced its workforce to a skeleton crew, operating in survival mode while seeking a buyer or an alternative strategic path forward.

It’s impossible to say exactly why Carisma ultimately closed shop. Perhaps if Moderna didn’t undergo its own cost-cutting plan in 2025, it could have kept Carisma alive long enough to bring their collaborative in vivo program to the clinic. Then again, maybe negative clinical data was simply insurmountable for a cash-strapped, early clinical-stage biotech in the lean funding years of the mid-2020s.

Yet, despite the Phase I result and the company’s ultimate demise, Carisma’s clinical trial data should not be overlooked.

Beyond testing safety and early efficacy, the trial collected tumor and blood biopsies from patients. Analysis revealed tumor microenvironment remodeling consistent with a broad immune response to the CAR-M treatment, which correlated with clinical response.

For the macrophage engineering community, though Carisma’s Phase I trial did not elicit tumor regression, evidence that CAR-Ms can remodel the tumor microenvironment is encouraging news.

Emerging players

The CAR-M field has attracted a resilient group of entrepreneurs and investors who continue to believe in, and invest in, the substantial promise of these cells as therapeutic tools.

Of the emerging companies in this space, one to watch closely is Create Medicines. This company recently closed a $122 million Series B, drawing considerable attention for its use of in vivo T cell engineering to treat autoimmune disease. But under the hood, Create’s most advanced clinical assets are actually in vivo-engineered CAR-Myeloid products. The company has already dosed patients in three Phase I trials with an mRNA-LNP platform to generate CAR-myeloid cells in vivo, targeting TROP2, GPC3, or HER2-expressing solid tumors.

Figure 3. CAR-M, CAR-Mono, and CAR-Myeloid therapies currently or previously in a Phase I clinical trial.

While Create Medicines is a private company and leadership has held early data close to the vest, there are early indications that their strategy is safe. One report from their first Phase I trial of an in vivo CAR-Myeloid product to target TROP2-expressing solid tumors suggests safe re-dosing of the mRNA-LNP, with only low-grade cytokine release syndrome and one case of immune effector cell-associated neurotoxicity syndrome (ICANS) at the highest dose.

It’s still too early to say if Create will avoid the negative clinical data that preceded Carisma’s demise. But there are promising signs: Create’s CEO, Dr. Daniel Getts, alluded to “an extremely compelling response profile” in the Phase I trial currently being run with another of their in vivo CAR-Myeloid products against GPC3-positive hepatocellular carcinomas.

If the Phase I data lives up to this early enthusiasm, the trial could provide the proof-of-concept the CAR-M field wants to see.

Such validation would benefit more than just Create. Other companies also aspire to bring engineered myeloid cells to the clinic and are not all limiting themselves to targeting solid tumors. Some of these companies include Deverra Therapeutics, Inceptor Bio, Resolution Therapeutics, and Calycia Bioscience.

“I think there’s a bigger community of people moving toward macrophages, slowly but surely, as we learn more about them,” says Daniel Greiner, cofounder of Calycia Bioscience.

These companies may be building on the ashes of Carisma—”I think Carisma definitely paved the way so that all of us can do what we’re doing,” Greiner adds—but they don’t believe they are sailing into the same storm.

Each company has its own strategies to avoid the obstacles Carisma faced, be it pursuing a different cell delivery method, targeting a different cancer antigen, or something else. But beneath these diverse approaches lies a common thread: sentiment in the CAR-M space seems to converge on the idea that macrophages may not win the solid tumor race alone. They may need some help from other cell types to fully realize their anti-tumor effects. This isn’t a slight to these powerful cellular machines, but rather a testament to their ability to bring out the best in their immune cell counterparts.

The power of teamwork

Carisma’s investigation of tumor remodeling by CAR-Ms demonstrated the potential for synergy between CAR-Ms and other immune cells, showing that engineered macrophages could recruit T cells to the tumor site. But those recruited T cells belonged to cancer patients whose immune systems were already failing to control their disease. What if, instead of relying on the patient’s compromised immune cells, CAR-macrophages could recruit other engineered immune cells that are primed to destroy the tumor?

“A dual targeting strategy could allow engineered myeloid cells to warm up the tumor, creating an environment where CAR-T cells can infiltrate. For solid tumor applications, this approach could be really powerful,” says Dr. Stefano Pierini, who led some of Carisma’s preclinical in vivo work.

Create Medicines has already capitalized on this idea, having recently begun a Phase I trial with a dual myeloid and NK cell-targeting in vivo CAR-engineering product, as well as a triple myeloid, NK, and T-cell-targeting product in preclinical development.

If the CAR-M story hints at anything so far, it may be that victory could require more than one cell type. Perhaps engineered immune cells need to stop racing against each other and start running together. Macrophages may not be destined for a solo act—they may simply need the right relay team.

Written By: Jodie Lunger (PhD student in the Department of Genetics, Stanford University)

Edited By:  Xingyu (Jasmine) Hu (PhD student in the Department of Biomedical Engineering, Boston University)