After a series of false starts, the continued improvement of traditional CAR-T therapies and surging interest in next-gen in vivo approaches, allogeneic CAR-T has entered a prolonged nuclear winter.\n Ever since 6-year-old Emily Whitehead became the first pediatric patient to receive CAR-T cell therapy in 2012, when T cells were removed from her body and reprogrammed to attack her leukemia before being reinfused, drug developers have tried to make the procedure more accessible to a broader range of patients.One way to bring CAR-T to the masses is to use readily available, prepackaged, off-the-shelf donor T cells, a so-called allogeneic approach, instead of the autologous method of using a patient’s own cells. But last year, companies started shifting their CAR-T cards to a novel method: in vivo CAR-T, where gene editing is used to generate CAR-T cells within a patient’s body.Leading cell therapy company Kite Pharma, a subsidiary of Gilead Sciences, scrapped a $2.3 billion allogeneic deal with Shoreline Biosciences in 2025 and instead started pumping money into in vivo, purchasing Interius BioTherapeutics for $350 million and inking a deal with Pregene Biopharma worth as much as $1.64 billion.While Kite Executive Vice President Cindy Perettie is always keeping her eyes on the allo field, right now she’s all in on in vivo.“We haven\'t seen the depth of response, the durability of response and the breadth of response today with allo in oncology,” Perettie told Fierce. With in vivo, though, Kite is seeing \"autologous-like responses.”Perettie is instead watching allo CAR-T’s potential in autoimmune diseases, an area being pursued by several companies—including Fate Therapeutics, Allogene Therapeutics, Roche, AvenCell Therapeutics and others—but is not as far along as allo for cancer. And there’s competition from both autologous and in vivo CAR-T in the autoimmune space, as well. Kyverna Therapeutics, for example, recently shared phase 2 data, priming its lead stiff-person syndrome candidate to be the first autologous CAR-T approved for an autoimmune disease.AbbVie has invested into in vivo as well, buying autoimmune-focused Capstan Therapeutics for $2.1 billion, while BMS bagged Orbital Therapeutics for $1.5 billion and AstraZeneca engulfed EsoBiotec for $1 billion. Even the federal government, at the same time it defunded other cutting-edge science, pledged hundreds of millions of dollars to in vivo gene editing research, including CAR-T.The deals have continued into 2026, with Eli Lilly snapping up Orna Therapeutics for $2.4 billion on Feb. 9. Orna\'s technology uses circular RNA to fashion in vivo CAR-Ts, with a focus on autoimmune diseases.Of course, Big Pharma hasn’t walked away from allogeneic CAR-T entirely. In addition to its in vivo moves, AstraZeneca also has a long-standing partnership with—and stake in—French allogeneic company Cellectis. Roche, meanwhile, bought allo outfit Poseida Therapeutics for $1.5 billion in November 2024.“We are uniquely positioning ourselves in the field of donor-derived (allogeneic) cell therapies,” a Roche spokesperson said in an email to Fierce Biotech. “Unlike traditional methods, these \'off-the-shelf\' solutions offer the potential for increased potency, improved safety and the scalability required to reach a significantly broader patient population.” ‘Valley’ of doubt Roche notwithstanding, broader trends in cell therapy have not been kind to allogeneic approaches. Andrew Schiermeier, Ph.D., the CEO of allogeneic company AvenCell, told Fierce that allo is in an exceptionally cold \"nuclear winter.\" “We\'re already in the gully or the valley, where enthusiasm for allo has really dissipated. It would be hard for me to think that it could get worse,” he said. Since its inception over a decade ago, allogeneic CAR-T has been a field of false starts. Schiermeier and everyone else interviewed for this story agreed that there’s only one thing that can prevent the modality from slipping into the footnotes of medical history.“The only thing that saves us is data,” he said. With interest in allo frozen, new autologous therapies continuing to emerge and cash flowing toward in vivo approaches, has the curtain closed on allogeneic CAR-T’s window of opportunity? Not so fast, say the leaders of multiple allogeneic biotechs. “2026 is our year,” André Choulika, Ph.D., CEO of Cellectis, told Fierce, adding that he expects “huge momentum” in the allogeneic CAR-T space by the end of the year. Choulika’s belief is backed by several key data readouts coming this year from his own company and other allogeneic specialists. Cellectis expects interim data from a pivotal phase 2 trial of lasme-cel, the biotech’s lead candidate for acute lymphoblastic leukemia, to read out in the fourth quarter of this year, Choulika said.Meanwhile, Allogene is anticipating data from its own pivotal phase 2 trial for its lead lymphoma program, cema-cel, at the beginning of the second quarter, CEO David Chang, M.D., Ph.D., told Fierce at the recent J.P. Morgan Healthcare Conference in San Francisco.And Allogene’s Bay Area neighbor, Caribou Biosciences, also has a key readout expected this year from a phase 1 dose expansion study of the multiple myeloma prospect CB-011. The company is hoping to launch a pivotal study for lead asset vispa-cel in relapsed or refractory B-cell non-Hodgkin lymphoma as soon as possible, CEO Rachel Haurwitz, Ph.D., told Fierce in a January interview. Cellectis, Allogene, Caribou and Roche’s Poseida represent a sort-of “old guard” of allogeneic CAR-T, largely attempting to improve upon an area where autologous approaches have already succeeded. That makes it hard for them to excite Daina Graybosch, Ph.D., an analyst at Leerink Partners who covers cell therapy.“They\'re still going after this hypothesis of ‘We\'re doing what auto does,’ but picking different settings or maybe going after a weaker product,” Graybosch told Fierce. “To me, the home run in allo is to do something that auto can\'t do.”“Allo still has a place where allo can do things that no other platform can do,” she added. But those areas are tough nuts to crack, “and that\'s why a lot of investors have given up on it.”Bob Valamehr, Ph.D., the CEO of Fate Therapeutics, agrees that 2026 will be a big year for allogeneic CAR-T, though he’s not optimistic for the future of traditional allo approaches. Fate is one company identified by Leerink Partners\' Graybosch as “taking allo to the next level,” though Valamehr told Fierce that the biotech prefers to call itself an off-the-shelf company. “In vivo has come to fruition, even though it seems [like a] ridiculous opportunity to pursue, because allo has not been worthwhile,” Valamehr said. Heated rivalryThough in vivo’s surge captured headlines last year, the stiffest competition that allogeneic CAR-T faces comes from established and emerging autologous approaches. Cellectis, Allogene and Caribou are all attempting to challenge approved autologous CAR-Ts head-on.The soonest readout from the three “old guard” companies is Allogene’s expected phase 2 data for CD19-targeting cema-cel in the second quarter. Allogene made a shocking move in January 2024, halting two trials of cema-cel in advanced lymphoma to instead launch a program using the CAR-T to eradicate residual disease in patients who have undergone six rounds of chemotherapy.The ability to use cema-cel after first-line chemo to prevent relapse would be “completely transformative,” Christine Cassiano, Allogene’s communications leader, told Fierce at JPM. Allogene also believes cema-cel could be “truly the first time in which CAR-T might be available in community cancer centers,” she added, where most patients receive care.At the time, analysts from William Blair called the move a “bold strategic pivot” that could help Allogene surpass rivals and “expand its total addressable market.”“I do think it was smart to go up for that frontline maintenance,” Leerink Partners’ Graybosch told Fierce. But Kite’s approved auto CAR-T Yescarta (axi-cel), which many on the Allogene team helped develop, is also being tested in first-line lymphoma, she noted.According to Graybosch, if Allogene succeeds, it will be due to its “clever trial strategy” and not because allo CAR-T has fully proven itself capable of fulfilling a unique role in medicine. Autologous CAR-T is also rapidly moving towards accessibility. Kite hopes that it and Arcellx’s next-gen multiple myeloma CAR-T anito-cel, one of the most hotly anticipated drugs set to launch this year, will be available in community facilities. Anito-cel and other earlier-stage auto CAR-Ts in Kite’s pipeline are meant to become “outpatient community-ready,” one-and-done therapies, Kite\'s Perettie told Fierce at the American Society of Hematology conference in December.Anito-cel is set to challenge Johnson & Johnson and Legend Biotech’s auto CAR-T Carvykti (cilta-cel), and both are the primary opponents for Caribou’s CB-011. Caribou’s lead program vispa-cel, meanwhile, will have to compete with a full roster of approved auto products, including Kite’s Yescarta and Tecartus (brexu-cel), Novartis’ Kymriah (tisa-cel) and BMS’ Breyanzi (liso-cel).Cellectis’ leukemia candidate lasme-cel, too, is up against an approved medicine in Autolus’ Aucatzyl (obe-cel). And another candidate, eti-cel, faces the same rogue’s gallery as Caribou’s vispa-cel.Even with competition so fierce, these allogeneic upstarts think their candidates more than stack up against their autologous rivals. “Our data with lasme-cel and eti-cel for leukemia and lymphoma are better than autologous CAR-T,” Cellectis CEO Choulika told Fierce. “These products are going to be approved. They\'re lifesaving.”Choulika highlighted lasme-cel’s potential in particular for patients that have been failed by all current therapies, like auto CAR-T Kymriah as well as Amgen\'s antibody Blincyto and Pfizer\'s antibody-drug conjugate Besponsa (inotuzumab ozogamicin). Lasme-cel, he said, gives patients a 35% chance of their cancer completely disappearing, setting them up for a bone marrow transplant. Graybosch admits that lasme-cel “might be better than brexu-cel from Gilead, but that product is way inferior to obe-cel from Autolus.” Obe-cel and brexu-cel have similar efficacy, but obe-cel has far lower rates of severe side effects. “So even if you\'re working post brexu-cel, do I care?” she asks.Meanwhile, Caribou’s strategy for vispa-cel is to try to skirt the autologous competition, CEO Haurwitz told Fierce.“Our clinical development has been focused on second-line, large B-cell lymphoma for several years now, and even within that population, you might imagine different strategies for how to ultimately run a pivotal study,” Haurwitz said. The FDA has encouraged Caribou to pursue the candidate\'s use in patients who aren’t eligible for autologous CAR-T or stem cell transplants, she said, which represents the majority of the second-line setting.The reason so many patients aren’t getting auto CAR-T comes back to the origin of why scientists started pursuing allogeneic approaches in the first place, Haurwitz said. The main benefits of allo are supposed to be that it is immediately available “off-the-shelf” when the patient needs it and that it doesn’t depend on a patient’s own T cells. “Many patients have garbage T cells, either because of the nature of their disease or the impact of the therapies that they\'ve previously received,” Haurwitz said. “Those patients will always need something from somewhere else to drive the anti-cancer activity.”Leerink Partners\' Graybosch questioned if CAR-T really needs to be given immediately. Many doctors like to give a bridging therapy to prepare their patients for CAR-T, she said, which means taking the time to wait for an autologous therapy to be prepared is no problem.Even in lymphoma, where there’s “less extreme need for bridging,” Graybosch said, “it’s not necessary to have anything faster than Yescarta,” which has a turnaround time of about two weeks.AvenCell CEO Schiermeier disagrees that doctors don’t want off-the-shelf options. AvenCell is another one of Graybosch’s “next-level” allo biotechs.Physicians “are absolutely dying to have an allo that works as well or better than auto,” he told Fierce. From the high cost to the need for healthy patient cells and a specialized center to administer the treatment, “some lamentably low percentage of patients who qualify for CAR-T are actually getting it.”When it comes to trashy T cells, autologous manufacturers are continuously improving their ability to pluck out the cream of the crop, Kite’s Perettie told Fierce in January.“We talk about that a lot,” Perettie said. When a patient sample arrives, “you do have the ability to select for better cells. Not everyone’s doing this in their manufacturing process, but that’s something that we think is really important and a place that we’ve focused on.”Targeting small slices of patients who have failed other therapies and can’t receive autologous CAR-T may be a solid strategy to secure the first FDA approval for an allo CAR-T, which Caribou leader Haurwitz notes “there is no playbook for.” But it’s harder to gin up industry excitement when you’re just nipping at the edges of auto’s success. When it comes to the initial dream of supplanting auto with donor-derived off-the-shelf alternatives, Graybosch sees little hope.“It’s not better in efficacy, and all the side things it was better at in the interim, autos improved on,” she said. “That’s the challenge for allo.” Long time comingBy Choulika’s account, Cellectis has been working on allogeneic CAR-T since before Emily Whitehead was ever treated with her ground-breaking autologous therapy. He co-founded Cellectis in 1999 on the back of his research on gene editing enzymes called meganucleases.“We finally dropped off meganucleases in 2010, 2011, when we licensed this technology from the University of Minnesota called TALEN,” Choulika recalled to Fierce. “We decided to go using gene editing and TALEN technology to engineer off-the-shelf CAR-T cells, because there was no business doing CAR-T cells at this time.”Whitehead’s treatment was later developed by Novartis and approved for acute lymphoblastic leukemia as Kymriah (tisa-cel) in 2017. Gilead’s then-recently acquired Kite wasn’t far behind, nabbing approval for Yescarta (axi-cel) in relapsed or refractory large B-cell lymphoma just a couple months later. Kite then secured the world’s first bona fide CAR-T franchise, with Tecartus (brexu-cel) approved for mantle cell lymphoma in 2020.In parallel with autologous CAR-T’s drumbeat of progress, new allogeneic ventures rose to try to innovate on the newborn modality.Allogene was launched in 2018 by former Kite CEO Arie Belldegrun, M.D., and Chief Medical Officer Chang, licensing 17 allo CAR-T assets from Cellectis through Pfizer. Caribou started as a CRISPR company spun out of the lab of gene editing pioneer Jennifer Doudna, Ph.D., in 2012 before pivoting to an allogeneic CAR-T pipeline around 2020. As of early 2026, there are seven FDA-approved CAR-T therapies, all for blood cancer indications and all autologous. Despite years of work, more than a decade in some cases, no allogeneic CAR-T has crossed the regulatory finish line.For Graybosch, this failure can be summed up with one word: pharmacokinetics.Because donor cells can be rejected by the patient’s body, “getting the right exposure remains a massive, challenging barrier,” Graybosch said. “Until you have an allo that gives you excellent, predictable, dose-responsive drug exposure, you haven’t solved that fundamental problem.”Schiermeier, the AvenCell CEO, compared allo to Elon Musk’s spaceflight startup SpaceX.“The first 50 times SpaceX tried to do a reusable rocket, they blew it up,” Schiermeier told Fierce. “CAR-T is very much an engineering problem, and we’re going to have to explode a few rockets.”But critically, Schiermeier pointed out, SpaceX didn’t keep trying the same kind of rocket over and over again. Instead, the company adjusted its approach until finally landing a reusable rocket in 2015. The AvenCell CEO thinks allogeneic CAR-T is the same, but has been dogged by companies persisting with outdated approaches.One of the first methods scientists used to try to protect donor CAR-T cells from being rejected by the recipient was eliminating a protein called beta2 microglobulin (B2M) from their surface, Schiermeier explained. B2M is a major component of a protein complex called MHC class I, which is found on all cells. T cells can recognize a foreign B2M and target the donor cell for destruction; without it, the allogeneic CAR-T cells should be able to slip past the patient’s immune system unseen and attack cancer cells.The problem, Schiermeier said, is that when another group of immune cells called natural killer (NK) cells encounter the CAR-T cell, the very same lack of B2M that wards off T cells triggers alarm bells.“If NK cells detect a cell that has no [MHC] class I showing up—it’s as smooth as a baby’s bottom—the NK cells will eliminate them,” he said. “Arguably, they do that even more aggressively than T cells.”Some companies then tried to fool the NK cells by engineering the CAR-T cells to express a “don’t eat me” signal, like CD47, Schiermeier said. But NK cells are diverse, “and they don\'t all recognize the same decoys.”Caribou is one company partially continuing down the B2M road. The biotech’s multiple myeloma candidate, CB-011, is engineered with B2M knocked out and decoy HLA-E added in.Roche’s two CAR-T candidates from Poseida also have B2M knocked out, a company spokesperson told Fierce. One candidate, RG6538, is being developed for multiple myeloma, while RG6540 is being tested in phase 1 trials for relapsed and refractory B-cell malignancies as well as autoimmune conditions.“We went down the B2M path for a very long time,” Schiermeier said of AvenCell, which was founded in 2021. “We ultimately decided that that was just not going to be a tractable idea.”AvenCell decided to only knock out a different part of the MHC class I molecule, while matching the remaining piece of it between the patient and the donor cells. This is enough to keep the NK cells off the CAR-T’s back, Schiermeier said.“We basically can match the entire U.S. population with about 20 unique donors,” he said. “That’s our special sauce.”AvenCell’s lead program is in acute myeloid leukemia (AML), a blood cancer where patients’ T cells are too exhausted for any autologous CAR-T to work effectively.“AML is still a place where I do really see the allo argument,” Leerink Partners’ Graybosch said. “Where the patients are just so sick and beat up.”No matter what genetic edits are used or which indication is pursued, all of these allo approaches need some level of preconditioning to make sure the engineered cells can survive long enough to replicate and destroy the cancer. For Fate’s Valamehr, this devastation of the patient’s immune system is a burden too big to ignore.“Majority of the traditional allo companies have leveraged conditioning chemotherapy to increase their efficacy,” Valamehr told Fierce. “It seems like traditional allo CAR-Ts are falling short and, to compensate and be comparable to auto CAR-T, need to boost up their chemotherapy use.”Fate’s phase 1 pipeline is built using CAR-Ts engineered from induced stem cells rather than donor cells, which can be stored in standardized batches. This approach allows Fate to make a high number of edits to the cells, as many as 13, Valamehr said, because once the edits are done, they don’t need to be made again in a different group of donor cells.“Once you do that initial engineering, and you have a master cell bank, your starting material is there for a very long time,” the CEO said. With all of those edits made to prevent the patient’s immune system and the CAR-T cells from coming into conflict, Fate sees no need for preconditioning.“Our clinical trials, when we have our edits, are actually without conditioning, or very low conditioning,” Valamehr explained. Fate, which originally launched in 2007, also went through a phase of attempting to knock out B2M in 2016, Valamehr said.Other allo leaders are concerned about the need for chemotherapy too. A patient in Allogene’s pivotal cema-cel trial died in August 2025 due to an antibody used for preconditioning. The biotech scrapped the antibody entirely afterward, and none of the company’s other trials are using it.Allogene and Fate both have CAR-Ts edited with an “offense is the best defense” approach. When the CAR-Ts are attacked by the patient’s immune system, they retaliate, killing the aggressing cell before they themselves are destroyed. While Allogene’s cema-cel doesn’t use the biotech’s version of this technique, called Dagger, an earlier-stage solid tumor candidate called ALLO-316 does.ALLO-316 “behaves almost like autologous CAR-T in terms of expanding and persisting in patients, and if anything, when you look at the numbers, it’s much better,” Allogene’s Chang told Fierce. “That’s why we believe that we can reduce the lymphodepletion.” Cold snapThe lack of a need for preconditioning is one of the theoretical benefits of in vivo CAR-T, along with the potential for easier administration and lower costs. But many of the allogeneic adherents interviewed by Fierce for this story spoke of dire concerns with their surging opponent. One form of in vivo CAR-T involves infusing gene editors into a patient’s body that modify the genome itself, inserting instructions that the T cells need to make the disease-targeting CAR (which stands for chimeric antigen receptor). This so-called integrating approach, the allo leaders warn, could cause mass chaos.“We’re not talking about billions or hundreds of billions of DNA fragments that are going to be injected,” Cellectis’ Choulika told Fierce, “but hundreds of trillions.” “Every oncogene in the human body will be hit one place or another,” he said. Resulting cases of cancer could cause a \"nuclear winter\" for in vivo technology, Choulika warned, using the same phrase AvenCell CEO Schiermeier employed to describe the current allo CAR-T landscape.Fate’s Valamehr, too, worries about the potential for in vivo viral vectors to stick parts of their DNA inside the patient’s genome, or for non-integrating lipid nanoparticle delivery systems to cause liver toxicity.The risk for genome tinkering to turn into tumors was brought into stark relief late last month, when the FDA placed two Regenxbio gene therapies on clinical hold. A patient in one of the trials developed a brain tumor four years after treatment; while the patient is doing fine now, a preliminary genetic analysis produced evidence that the viral vector used for the therapy, which isn’t a CAR-T, had integrated parts of its DNA into a known cancer gene.However, that patient is the only one to develop a tumor out of many thousands who have received the same kind of viral vector. And whether or not the vector integration actually caused the cancer to emerge remains an open question.Kite’s Perettie, for her part, isn’t concerned by a hypothetical in vivo nuclear winter. Like all new therapies, in vivo CAR-T is first going through smaller safety trials before being given to thousands of patients, she noted. And Kite hasn\'t noticed the vectors it acquired from Interius inserting DNA into the cell’s genome willy-nilly, she added. Because in vivo still needs to get through safety studies unscathed, allogeneic CAR-T has a big head start in the clinic, Allogene’s Chang said. This leaves him unworried about allo being leapfrogged by in vivo. But in reality, in vivo isn’t that far behind. EsoBiotec, the Belgian company AstraZeneca acquired early last year, shared data from a phase 1 multiple myeloma trial last summer, where four patients given a lentivirus-and-mRNA-based in vivo therapy responded to treatment, with the cancer of two patients resolving completely.And Kite plans to push its in vivo vectors from Interius into phase 1 trials this year, Perettie told Fierce. While the CAR-T pioneer will be careful with its in vivo advancement, just like in the early days of autologous, Kite so far doesn’t regret its choice to leave allo behind.\"We’re really excited about the early data we’ve seen,\" Perettie said. “We have made a conscious decision based on the data we saw to actually double down in in vivo.\"
