How Cell Therapies Help Fight Solid Tumors

The cutting edge of treating solid tumors with cell therapies got notably sharper this year.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd Wolchok and Michael Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, Betof Warner told Medscape Medical News. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” Betof Warner told Medscape Medical News. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, Betof Warner, who is not a part of these studies, told Medscape Medical News.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, Betof Warner told Medscape Medical News, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.

An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified for Medscape Medical News that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said, in the interview with Medscape Medical News. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” Betof Warner told Medscape Medical News. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, Betof Warner told Medscape Medical News.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” Betof Warner told Medscape Medical News. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.