When the U.S. approved the first tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma in 2024, it marked a turning point for a field that had spent decades on the margins of cancer research. Unlike conventional drugs, TIL therapies are built from a patient’s own immune cells. Doctors remove T cells present in a tumor, multiply them by the billions in a lab, and infuse them back into the body to mount a more powerful attack against cancer cells.
The idea has existed since the 1980s, but only recently has the technology and the clinical data caught up with the ambition. The 2024 approval for Iovance Biotherapeutics’ TIL therapy lifileucel, known under its brand name Amtagvi, was proof of this.
“For the longest time, people thought this is not something that can be commercialized. Now, it’s proof of principle that TIL therapy can be commercialized,” said Chantale Bernatchez, senior director of Cell Therapy Process Development at the cell therapy manufacturer CTMC. “It’s a big milestone.”
Iovance’s drug is an autologous therapy, meaning that the cells of a specific patient are removed from tumors, cultured, and reintroduced into the patient’s body. So, each lot of cells is for a particular patient, making it a personalized treatment. During the few weeks after infusion, only the infused cells are circulating in the bloodstream, giving them a head start on the rest of the immune cells.
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Iovance’s Amtagvi approval paves way for TIL therapy in solid tumors
It became the first non-chimeric antigen receptor (CAR)-T adoptive cell therapy to hit the market. In fact, this class of drugs is the first cell therapy to target a solid tumor. Unlike CAR-T, where cells are retrieved from the blood, TIL therapy takes T cell lymphocytes (white blood cells) from the tumor, where there is an abundance of these cells.
“If T cells recognize tumors, they’re more likely to be found in the tumor. However, if they are not controlling the tumor, that means their functions are somehow lacking, and they are being overcome by the tumor microenvironment. But they are usually found there, in a sort of suppressed state,” said Bernatchez.
Whereas in the blood, Bernatchez pointed out that only a small fraction of antitumor T cells is present. So, taking T cells from the blood and reinfusing them wouldn’t be as effective because these cells lack anti-tumor reactivity.
In the case of CAR-T therapy, these cells in the blood are withdrawn and engineered with a CAR, to make them recognize the tumor. This way, they bypass a typical T cell response and can spot the same antigen on a tumor. And so, these CAR-Ts “become super activated, super highly efficient killers,” Bernatchez explained. However, this comes with a downside.
If the tumor were to lose the only target that the CAR recognizes, it could evade the attack and continue to grow. That’s where TIL therapy come in. TILs can target a slew of antigens, although we aren’t aware of which antigen they are targeting.
“It’s specific to every patient,” said Bernatchez. “The tumors tend to contain mutations that are recognized by the immune system. So, a lot of the T cells infiltrating the tumor recognize those mutations, but each patient has a different set of mutations. So, with TIL, we have the ultra-personalized T cell therapy because it’s created for you and only recognizes your tumor. With CAR-T, it’s also created for you with your T cells, but we will engineer them to recognize an antigen that is expressed on tumors from most patients.”
And as TILs recognize more antigens, it makes it harder for tumors to develop resistance against them.
Moreover, CAR-T therapy was initially developed to treat blood cancers. While it has been successful in doing so, T cells in the blood rarely migrate to the tumor. So, the likelihood of it combating solid tumors is rather low. TILs on the other hand, have greater efficacy when dealing with solid tumors.
“While CAR-T therapies are clinically established in hematologic cancers, their efficacy in solid tumors – particularly immunologically cold tumors – remains unproven due to challenges such as limited tumour infiltration, antigen heterogeneity, and complex multi-step manufacturing processes. TIL therapies overcome these barriers by using naturally tumour-adapted T cells that can effectively infiltrate the tumour microenvironment and, through their polyclonal nature, recognize multiple tumour antigens, thereby reducing immune escape and improving outcomes in heterogeneous cancers,” said Jonas Båtelson, chief executive officer (CEO) and co-founder of TIL therapeutics company CuraCell.
Prior to being dosed with a TIL, Bernatchez explained that patients are given chemotherapy to wipe out the immune cells from a patient’s blood so that the infused cells have a lot of space to expand into. Then, by exploiting the body’s ability to recognize tumor cells, T cells that have been reinfused into the patient identify and target the tumor.
“Basically, it’s a one-time therapy,” said Bernatchez. “It’s not a drug that you would repeatedly take; it’s just the one time. The patient will stay in the hospital until the white blood cell count in the blood rises back and the platelets come back, because the type of lymphodepletion that the chemotherapy does is transient. So, the bone marrow will reconstitute new immune cells that are eventually going to reconstitute the blood fully.”
Patients who are given Amtagvi, however, also need to be dosed with high-dose interleukin 2 (IL2) immunotherapy. This is supposed to stimulate the body’s immune cells to recognize and kill cancer cells, and in combination with Amtagvi, the regimen is designed to induce a heightened response. But IL2 can trigger neurotoxicities, although these side effects can be managed.
Engineering TILs: Obsidian Therapeutics’ OBX-115 and KSQ Therapeutics’ KSQ-001EX move ahead
However, Obsidian Therapeutics, one of the biotechs that Bernatchez’s CMTC has been in a long-standing partnership with, has figured out a way to avoid dosing with IL-2 altogether. Its lead candidate, OBX-115, is genetically modified to produce a cytokine called IL15, which is membrane-bound. Cytokines are small proteins critical in controlling the activity of immune cells responding to cancer. According to Massachusetts-based Obsidian, this is designed to eliminate the need to co-administer high-dose IL2, thereby circumventing neurotoxicities associated with it.
“I really think that we’re looking at the next wave of TIL therapy products that are going to be engineered, and hopefully, either more potent or reducing toxicity of the regimen.”
The therapy OBX-115 is born out of Obsidian’s cytoDRiVE platform that involves drug responsive domains (DRDs). These are engineered molecules that act as molecular switches to stabilize a payload protein in the presence of small molecules.
Preclinical data found that engineered, membrane-bound IL-15 TILs such as OBX-115 are more effective than conventional, un-engineered TILs that require IL-2 dosing against melanoma. Phase 2 results of the ongoing clinical study will be presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in May.
Another biotech developing non-traditional TIL therapies is KSQ Therapeutics, also located in Massachusetts. KSQ uses CRISPR/Cas9 technology – a gene editing tool that cuts and alters DNA – to edit TILs to improve their ability to fight solid tumors. The lead candidates knock out specific genes, such as SOCS1 and Regnase-1. SOCS1 is a negative regulator of T cell signaling by cytokines and regnase-1 is an endonuclease – an enzyme that cuts DNA – that regulates immune responses by degrading mRNA of pro-inflammatory proteins.
KSQ’S lead candidate KSQ-001EX inactivates SOCS1 and its other clinical candidate and KSQ-004EX targets Regnase-1 and SOCS1. Both in phase 1/2 trials at present, KSQ-001EX is being tested against melanoma, non-small cell lung cancer (NSCLC), and head and neck squamous cell carcinoma (HNSCC), and KSQ-004EX for melanoma, NSCLC, HNSCC, pancreatic cancer, colorectal cancer, and cervical cancer.
“I really think that we’re looking at the next wave of TIL therapy products that are going to be engineered, and hopefully, either more potent or reducing toxicity of the regimen,” said Bernatchez.
CuraCell advances TIL therapy for prostate and colorectal cold tumors
While melanoma seems to be the top priority for most TIL therapy developers at the moment, Båtelson’s CuraCell could be the first to take on prostate cancer. Its prime candidate CC-38 is being developed to address immunologically ‘cold’ solid tumors. These are cancers that are highly resistant to current immunotherapies and tend to show limited immune activity. TIL therapies, according to Båtelson, have been found to target these hard-to-treat solid tumors.
“At Krankenhaus Nordwest Hospital in Frankfurt, 11 patients with cold solid tumors were treated with an experimental TIL product under patient named use. These observations demonstrated that TILs can induce clinically meaningful and durable responses even in refractory, poorly immunogenic tumors,” said Båtelson.
He explained that CuraCell built on these findings to develop its CytoPLY platform to generate highly potent, polyclonal, and persistent tumor reactive T cells.
“This approach has resulted in CC-38, which is now in an organized phase 1 clinical trial that evaluates the potential for treating cold solid tumors with TILs,” said Båtelson.
The phase 1/2a trial is in late-stage prostate and colorectal cancer, targeting indications with significant unmet need and historically low responsiveness to immunotherapy, explained Båtelson.
“The study incorporates a differentiated repeated dosing strategy designed to enhance T-cell persistence, deepen responses, and improve long-term clinical outcomes. With integrated immune monitoring and translational analytics, the trial aims not only to demonstrate safety but also to refine and optimize TIL therapy for cold tumor settings,” said Båtelson.
TIL therapy development: progress has been a mixed bag
Developing TIL therapies is no mean feat, considering the track record hasn’t been great. British company Achilles Therapeutics dropped its cell therapies program and was shuttered in 2024, Zombie biotech buyer Xoma Royalty acquired cash-strapped Turnstone Biologics last year, and Texas-based Instil Bio dumped its pipeline earlier this year.
And while Amtagvi’s FDA clearance opened doors for the field, the price of TIL therapies may be a concern for many. Priced at $515,000 per patient, the one-time therapy is slightly more expensive than CAR-T therapies, which cost around $500,000 for people with blood cancers.
Nevertheless, now that TILs have been approved for melanoma, there is hope that they could be greenlit for other solid tumors in the future. And, as more biotechs make headway, prices could come down and so could dosages. Bernatchez believes that the field has come a long way.
“It took a long time because of how cumbersome this therapy was at the beginning. Now, a lot of progress is being made in streamlining the manufacturing of TIL, making it easier.”
For Båtelson, the approval of TIL therapies represents a “pivotal inflection point,” specifically in the case of cold solid tumors, “demonstrating that effective cell therapy can extend beyond immunologically ‘hot’ cancers like melanoma to address the far larger and more challenging population of ‘cold’ tumors, which comprise approximately 80 to 90% of solid cancers.”
He said: “Beyond its scientific significance, such a milestone could open the door to new safe, effective, and scalable treatment options across a wide range of cancers, positioning TIL therapy as a foundational platform in mainstream oncology.”
