How In Vivo CAR T-Cell Therapies Could Rewrite the Cancer Care Playbook

During her honeymoon in Papua New Guinea, one thought kept occurring to Michelle Lynn Hall, PhD, as she hiked through remote villages: in vivo chimeric antigen receptor (CAR) T-cell therapies could drastically improve access to care.

Michelle Lynn Hall, PhD | Image: LinkedIn

Hall, an associate vice president at Eli Lilly, oversees nanomedicine, which includes the development of therapies that can prompt cells to manufacture medicine in vivo, or in the body. Such technology could have a profound impact not only on the rural, low-income communities that she visited during her trip, but also on patients who can’t access existing therapies.

“They don’t have access to antibiotics, antifungals, band aids—sometimes no clean drinking water. Forget a refrigerator,” Hall said. “So, this would be game-changing.”

Since debuting in 2017 with the approval of tisagenlecleucel (Kymriah; Novartis) and axicabtagene ciloleucel (Yescarta; Kite/Gilead),1,2 CAR T-cell therapies have transformed the treatment landscape. Clinical trials and real-world studies show that these therapies can induce durable remissions in patients with certain blood cancers who have exhausted other options, and more than 34,000 patients worldwide have now received a CAR T-cell treatment.3

But for all its promise, CAR T-cell therapy has remained a treatment for the few: only those who can travel to specialized hospitals, endure lengthy waits, and navigate a maze of logistics. In vivo treatments would eliminate all that. Although the field is still very early in development, companies such as Beam Therapeutics and Verve Therapeutics have published clinical trial data showing how analogous in vivo gene therapies can be successful for rare diseases and heart conditions. Drug developers are trying to apply this technology in cancer treatment.

The CAR T Bottleneck
CAR T, as it exists today, demands a complex process. Cells are collected from the patient, engineered in a laboratory, shipped back, and infused, usually after weeks of waiting. Patients then have to remain near the hospital for weeks with a caregiver in case any serious adverse effects (AEs) emerge.

In a study at Memorial Sloan Kettering Cancer Center in New York, New York, investigators found that less than 60% of patients referred for CAR T received it.4 Rapid disease progression, lack of available products, and concerns about AEs were the most common barriers. Black patients were statistically less likely to receive CAR T, exposing another layer of inequity.4

The lack of access is compounded by geographic barriers. A 2024 McKesson report found that millions of individuals in rural America have limited access to cell and gene therapies,5 living in “CAR T deserts.” Two-thirds of oncologists surveyed by the organization agreed that these therapies aren’t easily accessible to eligible patients. The most common barriers, according to the results, were insurance, out-of-pocket costs, and distance to a treatment center.

Joe DePinto, MBA | Image: McKesson

Joe DePinto, MBA, head of McKesson’s InspiroGene division, said that although improvements have been made in shortening the “brain to vein” time, or how long it takes from the moment a physician decides to order CAR T to the time a patient is infused, many logistical hurdles remain.

“The science is remarkable, and it’s really strong, but it adds to some complexity in how you deliver the product,” DePinto said. “The community hospitals would like to do it, but they don’t have the same infrastructure and the financial and personnel support [as] the academic centers.”

Financial Toxicity
Payer hurdles and financial toxicity further amplify access gaps, DePinto said. Oncologists interviewed for McKesson’s report cited insurance coverage and out-of-pocket costs as the leading reasons eligible patients are steered away from CAR T-cell therapies and toward more traditional treatments. Even patients with health insurance can face lengthy prior authorization processes, outright denials, or surprise bills related to travel and ancillary care.

Although a variety of payment models are under discussion by government officials, drug manufacturers, and payers, the lack of standardized reimbursement for advanced therapies continues to stymie equitable access, especially for those in lower-income brackets or with less robust benefits.

The complexity of the journey for patients seeking CAR T-cell therapy is another layer of inequity. For many, successfully navigating the referral, enrollment, and administration process requires the persistent involvement of patient advocates, caregivers, and clinical navigators, according to a May 2025 report on advanced therapies by Cardinal Health.6 Patients with strong “squeaky wheels,” or advocates who can persist through the logistics hurdles, have better outcomes, the report noted. The report detailed the story of Bradley Watts, who was diagnosed with follicular lymphoma and diffuse large B-cell lymphoma at age 29 and underwent several treatments between 2017 and 2020 before trying CAR T.6

“My support network was massive and significant in many ways, so I could solely focus on receiving treatment,” Watts said in the report. “A lot of pieces were delegated to my mom and significant other, as well as others, so that I could focus on my treatment.”

Lowering the Barrier
Pete Robinson, MBA, of the research company Novotech, said CAR T-cell therapies require a lot of heavy lifting by companies and health systems looking to administer them. They must juggle institutional review boards, biosafety committees, product handling, and logistics such as cold chain storage. They also need staff available on site to manage the therapies properly and deal with patients’ AEs.

“That’s a pretty elaborate process,” he said. “That’s why in vivo CAR T is another really big step forward.”

He described in vivo CAR T-cell therapies as the third generation of the therapies, with autologous versions, or ones that use a patient’s cells, as the first generation, and allogeneic, or off-the-shelf CAR T made from donor cells, as the second generation.

New Technologies
In vivo CAR T offers a new path. Instead of engineering cells outside the body, in vivo CAR T sends the instructions for making the medicine directly into the patient, letting their cells do the work. There are 2 approaches: viral vectors and nonviral methods such as lipid nanoparticles (LNPs), which use a delivery platform similar to messenger RNA (mRNA) COVID-19 vaccines. Both are designed to cut out the cell harvesting, laboratory manufacturing, and extended hospital stays that come with today’s CAR T.

With viral vector delivery, engineered viruses carry the genetic instructions into a patient’s T cells, typically targeting the immune system in a precise way. Nonviral methods use LNPs—tiny fat bubbles that protect and transport mRNA or DNA—to deliver those same instructions directly to the patient’s immune cells.

Adrian Bot | Image: LinkedIn

“These are the 2 major technologies right now in clinical stage,” said Adrian Bot, chief scientific officer and executive vice president of research and development at Capstan Therapeutics, a company developing in vivo cell therapies that will be acquired by AbbVie.7 “There are variations, combinations, and permutations that are coming in preclinical stage, and longer term, I can envisage gene editing systems actually packaged up in appropriate vehicles for, let’s say, achieving more spatial-temporal control of CAR expression eventually in vivo.”

Even Out the AE Profile
Another significant hurdle for expanding existing CAR T-cell therapies beyond large academic medical centers is the potential for dangerous AEs, including cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome. Until recently, the FDA required patients to remain within driving distance of the medical center that administered their CAR T for 4 weeks post administration, in case AEs occurred. On June 26, 2025, an updated FDA policy reduced that period to 2 weeks.8

Luke Walker, MD | Image: Umoja

Luke Walker, MD, chief medical officer at Umoja Biopharma, another company developing in vivo cell therapies, said these treatments should, in theory, not spur the same severe AEs as traditional CAR T-cell therapies. The rationale is that in vivo therapies would have a longer ramp-up time, as the medicine would be created by the body at a slower pace compared with an infusion of the manufactured cells, though clinical trials will need to bear that out.

“The hope here is that you’d be able to even out that adverse event profile, where you don’t have that big spike of a high-risk toxicity early on, and that these are truly manageable in an outpatient setting,” Walker said. “And you combine that with a much lower cost of goods, and you can see a product that would be usable not only in an outpatient setting in the United States, but globally as well.”

Since most patients with cancer receive care in the community setting,9 this would remove a significant obstacle, he said.

“This is really just the first step, assuming that the in vivo approach will be successful,”

Walker said. “You get rid of the apheresis and the manufacturing piece; the next piece is going to be making sure that we can successfully give these [treatments] in less-advanced clinical settings.”

Hot Sector
Investor and pharmaceutical interest in in vivo CAR T-cell therapies is heating up, highlighted by AstraZeneca’s $425 million upfront acquisition of EsoBiotec in March 2025,10 with additional milestones potentially bringing the total to $1 billion. EsoBiotec’s lead in vivo CAR T-cell therapy candidate for multiple myeloma is already in early clinical trials in China, and the company is planning to expand into autoimmune indications.11

“This deal highlights growing pharma interest in in vivo CAR T, with companies advancing lentiviral or mRNA-based approaches for efficient CAR T programming,” analysts at banking firm Jefferies wrote.

Others, like Capstan, have received funding from blue-chip companies such as Eli Lilly; Bristol Myers Squibb; and the venture arms of Johnson & Johnson, Bayer, Novartis, Pfizer, and others.12 On June 30, AbbVie announced plans to acquire Capstan for $2.1 billion.7

Capstan’s mRNA lipid nanoparticle approach is similar to what competitors Orna Therapeutics and Myeloid Therapeutics are using,13,14 in contrast to lentiviral-based platforms used by Umoja, Interius BioTherapeutics, and Kelonia15-18 These therapies “have the potential to revolutionize the treatment paradigm of cell therapies in oncology and autoimmune by eliminating the need for lymphodepletion and ex vivo T-cell manufacturing,” Jefferies analysts wrote.

Misinformed Public
One unexpected challenge some of these medicines may face is pushback from lawmakers and groups trying to ban mRNA medicines, under the false belief that they cause significant changes to human DNA19 This strand of controversy started during COVID-19 and has picked up steam, with several US states considering steps to criminalize possession or distribution of mRNA therapies with up to 20 years in prison, although no laws have been enacted.

Beyond Cancer
Another benefit of in vivo CAR T-cell therapy is that it could make these treatments possible for diseases where traditional CAR T is just too toxic. Capstan’s Bot said that in vivo CAR T-cell therapies can be designed to work in the body for only a short time, rather than sticking around permanently.
By eliminating the need for preconditioning chemotherapy, as well as avoiding permanent immune cell modifications, in vivo CAR-T therapies could be used safely in a much wider range of indications—including first-line cancer treatment, autoimmune disorders, and even in outpatient settings where safety standards must be higher than in advanced oncology care.
“One aspect that is lost in translation is the fact that in vivo CAR T-cell therapy is just, in my opinion, the entry point to the broader concept of in vivo reprogramming of the immune system, so you can do so many other things,” Bot said. “This is just basically scratching the surface right now.”

References
1. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. Updated September 7, 2017. Accessed July 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome

2. NCI staff. With FDA approval for advanced lymphoma, second CAR T-Cell therapy moves to the clinic. National Cancer Institute. October 25, 2017. Accessed July 24, 2025. https://www.cancer.gov/news-events/cancer-currents-blog/2017/yescarta-fda-lymphoma
3. ISCT leads global scientific consortia to respond to recent FDA report on risk of T-cell malignancy in patients following CAR T-cell immunotherapies. Telegraft Hub. January 9, 2024. Accessed July 24, 2025. https://www.isctglobal.org/telegrafthub/blogs/lauren-reville/2024/01/09/isct-leads-global-scientific-consortia-to-respond
4. Valtis Y, Chin KK, Nemirovsky D. Barriers to chimeric antigen receptor T-cell therapy. JAMA Oncol. 2025;11(7):781-784. doi:10.1001/jamaoncol.2025.1127
5. 2024 Cell and Gene Therapy Report: Advancing the Future of Medicine. InspiroGene by McKesson. November 10, 2024. Accessed July 24, 2025. https://inspirogene.com/2024cgtreport/
6. Cardinal Health releases new report on the cell and gene therapy industry. Cardinal Health. May 7, 2025. Accessed July 24, 2025. https://newsroom.cardinalhealth.com/2025-05-07-Cardinal-Health-releases-new-report-on-the-cell-and-gene-therapy-industry
7. Santosh C. AbbVie to buy Capstan Therapeutics for $2.1 billion. Reuters. June 30, 2025. Accessed July 24, 2025. https://www.reuters.com/legal/transactional/abbvie-buy-capstan-therapeutics-up-21-billion-2025-06-30/
8. FDA eliminates risk evaluation and mitigation strategies (REMS) for autologous chimeric antigen receptor (CAR) T cell immunotherapies. FDA. June 26, 2025. Accessed July 24, 2025. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-eliminates-risk-evaluation-and-mitigation-strategies-rems-autologous-chimeric-antigen-receptor
9. Castine MJ III. The benefits of clinical trials at a community practice. American Oncology Network. May 25, 2021. Accessed July 24, 2025. https://www.aoncology.com/2021/05/25/the-benefits-of-clinical-trials-at-community-practices
10. AstraZeneca to acquire EsoBiotec to advance cell therapy ambition. AstraZeneca. March 17, 2025. Accessed July 24, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/astrazeneca-to-acquire-esobiotec.html
11. EsoBiotec begins clinical trial of in vivo BCMA CAR-T candidate ESO-T01
for multiple myeloma. EsoBiotec. December 11, 2024. Accessed July 24, 2025. https://www.esobiotec.com/press-release-investigator-initiated-trial/
12. Capstan Therapeutics announces $175M oversubscribed Series B financing. Capstan Therapeutics. March 20, 2024. Accessed July 24, 2025. https://www.capstantx.com/press-releases/capstan-therapeutics-announces-175m-oversubscribed-series-b-financing/
13. Orna Therapeutics presents new preclinical data supporting its in vivo CAR therapy approach in autoimmune diseases at the American Society of Gene and Cell Therapy Annual Meeting. Orna. May 15, 2025. Accessed July 24, 2025. https://www.ornatx.com/orna-therapeutics-presents-new-preclinical-data-supporting-its-in-vivo-car-therapy-approach-in-autoimmune-diseases-at-the-american-society-of-gene-and-cell-therapy-annual-meeting/
14. Myeloid Therapeutics unveils first-in-human in vivo mRNA CAR data, marking a breakthrough in RNA-based immuno-oncology at the 2025 ASCO Annual Meeting. Myeloid Therapeutics. May 30, 2025. Accessed July 24, 2025. https://myeloidtx.com/myeloid-therapeutics-unveils-first-in-human-in-vivo-mrna-car-data-marking-a-breakthrough-in-rna-based-immuno-oncology-at-the-2025-asco-annual-meeting/
15. Pioneering in vivo CAR T cell therapies. Umoja Biopharma. Accessed July 24, 2025. https://www.umoja-biopharma.com/
16. Making genetic medicine a reality for everybody. Interius BioTherapeutics. Accessed July 24, 2025. https://interiusbio.com/
17. Delivering on the promise of genetic medicine for every patient. Kelonia. Accessed July 24, 2025. https://keloniatx.com/
18. Peter RM. The in vivo revolution: how Interius, Umoja, and Vyriad are transforming CAR-T cell therapy. Labiotech. January 10, 2025. Accessed July 24, 2025. https://www.labiotech.eu/trends-news/first-ever-in-vivo-car-gene-therapy-clinical-trial-europe/
19. Flinn R. Proposed mRNA bans alarm scientists and startups. Cure. May 14, 2025. Accessed July 24, 2025. https://wewillcure.com/insights/therapeutics/proposed-mrna-bans-alarm-scientists-and-startups