Cell therapy for solid tumors pushed the boundaries in 2024
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It’s only the beginning.
That common refrain echoed throughout the oncology community in February when the FDA approved the first cellular therapy indicated in the United States for solid tumors, a tumor-infiltrating lymphocyte (TIL) therapy to treat melanoma. But leaders in the field have been quick to emphasize they consider it a major first step, not a culmination.
Source: Massachusetts General Hospital Cancer Center
That optimism remains pervasive among investigators exploring whether TILs and chimeric antigen receptor T-cell therapy — only approved in the U.S. for hematologic malignancies — can provide transformative benefits for malignancies beyond their current indications.
“I’m very excited about this approach to treating cancer. I see it as the approach most likely to result in significant improvements,” Steven A. Rosenberg, MD, PhD, senior investigator in NCI’s Center for Cancer Research, chief of the NCI Surgery Branch, and professor of surgery at Uniformed Services University of Health Sciences and George Washington University School of Medicine and Health Sciences, told Healio.
“In many ways, I feel like we’re just getting started now in the application of cellular therapy to the common cancers that result in 90% of all cancer deaths — the solid epithelial cancers,” he added. “It’s just the beginning of what I think is going to be a glorious future for cellular therapy.”
Results of several studies released over the course of 2024 — focused on use of cell therapies for brain tumors, sarcoma and kidney cancer — suggest the positive outlook on solid tumors is not without merit.
Healio | Cell Therapy Next spoke with investigators about the efficacy observed in these preliminary trials and how the insights gleaned have moved the field closer to understanding the potential of cell therapy for solid tumors.
TILs outside of melanoma
Multiple studies are being conducted into the impact of TILs on other cancers outside of melanoma.
In 2021, a phase 1 trial using TILs for metastatic lung cancer included 13 evaluable patients, and of those, three had confirmed responses and 11 saw a decrease in tumor burden.
“That really was the first evidence that you could take TILs beyond melanoma and show good response in a subset of patients with non-small cell lung cancer,” James J. Mulé, IPhD, immunologist and associate center director of translational science at Moffitt Cancer Center, told Healio. “Again, these were patients who had failed all other treatments.”
Mulé also mentioned work by another colleague at Moffitt, Shari Pilon-Thomas, PhD, an immunologist currently evaluating use of TILs in bladder cancer, and another researcher’s work in women with cervical cancer.
“We do know that you can use T cells to identify antigens on the solid cancers in up to 80% of all patients with metastatic solid cancers,” Rosenberg said. “We’ve published the effective treatment of patients with breast, cervical, colon or liver cancers.”
Whether TILs can be effective treatment for solid tumors is a question asked and answered in the affirmative, according to Rosenberg. The expansion of TILs as a treatment modality faces another obstacle, he added.
“The challenge now is in figuring out ways to generate cells of sufficient reactivity with sufficient proliferative capacities that will mediate tumor regression in a larger percentage of patients,” he said.
Rosenberg and Mulé believe challenges can be overcome, and cellular therapy will grow into a foundational piece of solid tumor treatment, along with surgery, radiation and chemotherapy.
“When it comes to immunotherapy, one of the most important findings that we’ve made in the last several years is an understanding of the targets of the immune system on the cancer,” Rosenberg said. “The fact that we can now, today, identify T cells that recognize a cancer in 70% to 80% of all patients with metastatic cancer holds substantial optimism for the ability to take advantage of that in developing new treatments. One of the advantages of cell therapy — it’s a living drug. When we inject those lymphocytes that can recognize the cancer, they expand thousands-fold in the first week or 2 after they are injected.
“I see immunotherapy playing a very important part of the future of cancer treatment in addition to the standard treatments,” he added. “I’m a surgeon, and probably 80% of people who can be cured of cancer today are cured by surgery. I don’t expect the current methods to be completely replaced, but I do see immunotherapy adding to treatment either in conjunction with other modalities or as a standalone treatment.”
Hope in glioblastoma
Multiple studies looked at glioblastoma and CAR T-cell therapy, showing significant progress with novel delivery methods.
In a safety run-in cohort, where researchers administered a single dose of CARv3-TEAM-E cells (CAR-TEAM) and monitored patients for toxicity, changes were seen within a day.
“We honestly didn’t expect much to happen, though of course we were nervous and hopeful,” Marcela V. Maus, MD, PhD, director of the cellular immunotherapy program at Massachusetts General Hospital Cancer Center and a Healio | Cell Therapy Next Associate Medical Editor, told Healio.
“Within 12 hours of giving the cells into the fluid around the brain, the patients developed fever and then altered mental status,” Maus added. “We were very surprised to see those changes in the tumor on the MRI as early as 24 hours after treatment.”
No effective treatments exist for glioblastoma, but CAR-T can be an effective approach, Maus said.
“T cells are living drugs that can actively migrate into tissues,” Maus said. “CAR T cells can theoretically overcome ... barriers. We can redirect to a specific antigen, thus bypassing ‘natural’ immune responses, and — in this case — we can put them in the fluid around the brain, thereby increasing their chances of getting to the brain tumor itself.”
The CAR-TEAM approach — which combines CAR T cells and bispecific antibodies — targets wild-type EGFR, which is expressed in more than 80% of glioblastoma cases.
“The trick is that it’s also expressed in other healthy tissues, like the skin, lungs and gut,” Maus said. “We devised a system to have CAR T cells target a very specific mutated antigen in glioblastoma — EGFRvIII — but also secreting a T-cell engager antibody molecule (TEAM). This allowed us to open a therapeutic window where the TEAM molecules target the brain tumor but quickly fall off any T cells that enter the blood and ultimately get cleared by the kidneys.”
Enrollment on this trial will continue. Researchers intend to assess low-dose chemotherapy as a conditioning regimen, as well as whether multiple infusions improve response durability.
“We are hopeful that this kind of multi-engineering of T cells will also be able to have therapeutic effects in other solid tumors,” Maus said. “There are various CAR-Ts that are already approved in lymphoid malignancies, but this kind of ‘standard’ design has not been as effective in solid tumors. Further engineering of the T cells offers that hope.”
In another glioblastoma trial, all six patients achieved tumor reduction within 2 days of receiving the CAR-T.
“These results exceeded our expectations,” Stephen J. Bagley, MD, MSCE, section chief of neuro-oncology at Penn Medicine, told Healio.
The novel CAR-T targets EGFR and interleukin-13 receptor alpha-2 (IL13Ra2) tumor-associated antigens.
Because EGFR alterations occur in 50% to 60% of patients with glioblastoma, and IL13Ra2 appears in approximately 75%, attacking both could be a promising approach, Bagley said.
“You’re statistically increasing the likelihood that a given patient is going to have at least one of our targets, if not both,” he added.
In prior trials, researchers administered CAR-T via IV. This time, they did so intrathecally, directly into the spinal fluid.
“With intrathecal delivery, you’re essentially delivering cells directly into the central nervous system. You are making it much easier for the CAR T cells to encounter tumor cells more readily and more quickly,” Bagley said.
The dual-targeting and a new delivery system produced rapid results.
“We’re getting a hint of durability in some of our patients, but it’s early days,” Bagley said. “All we can say so far is that there is clearly a signal.”
Every study participant developed neurotoxicity within 72 hours of treatment, sometimes as early as 8 hours.
“We don’t want patients to be sick, obviously,” he said. “We don’t want them to experience symptoms, but the wealth of years of experience giving CAR T cells to patients with hematologic malignancies like leukemia and lymphoma have shown us that when these cells are active and they’re actually exerting meaningful antitumor effects, it often comes with substantial toxicity.”
Multivalent targeting and local delivery could help researchers investigate treatments for other solid tumors, Bagley said. In glioblastoma, however, one key will be earlier implementation of effective therapies.
“There are a lot of challenges with treating patients when the tumor has already grown back,” Bagley said.
‘Big deal’ in sarcoma
A novel immunotherapy using HER2-specific CAR T cells produced clinically beneficial results for multiple individuals with advanced sarcomas, according to results of a phase 1 trial published in Nature Cancer.
Half of the 14 enrollees in the HEROS 2.0 trial achieved either complete response or stable disease.
“For a disease like this, especially in children, any progress we can make and anything you can learn from these kinds of studies will help us make a difference in the future,” Meenakshi G. Hegde, MD, associate professor in the department of pediatrics at Baylor College of Medicine and Texas Children’s Hospital, told Healio. “[Although] this is not a home run — we didn’t cure everybody we treated — we learned a lot, and we were able to help some patients.”
Sarcomas can be “complex” malignancies, Hegde said, noting she has found “pieces of bone in the lungs” in patients with osteosarcomas.
“If you look at the last 2 or 3 decades, there is no progress [in sarcoma treatment],” she said. “We are stuck.”
Targeted therapy could be an answer.
In HEROS 2.0, researchers enrolled individuals with HER2-expressing sarcoma who had recurrent or refractory disease after standard first-line therapy.
Investigators observed HER2 CAR-T expansion following 19 of 21 infusions. Half of enrollees derived clinical benefit — 21% achieved complete response and 29% exhibited stable disease lasting up to 8.7 months. The rest had progressive disease after the 6-week evaluation period.
“To see that there was some benefit in this cohort of patients for me is a big deal, and I’m sure it was for these parents, too,” Hegde said.
Cytokine release syndrome occurred in 79% of participants, and those who received fludarabine plus cyclophosphamide had more severe cases.
Hegde believes understanding what works in cellular therapy comes down to three factors — the host, the tumor and the product. Unfortunately, she said, solid tumor patient populations often are heterogeneous.
“I don’t have enough osteosarcomas to run any of these analyses meaningfully — to identify who these patients are — or enough rhabdomyosarcomas,” Hegde said. “That’s a big challenge. Until we can show some more evidence it is going to have some efficacy, I think these are the kind of studies you will see because patients come when they’re very advanced.”
Hegde thinks she and her colleagues are on the right path, but more work needs to be done.
“I do not believe CAR T cells alone will be the answer,” she said. “I think they will be part of the answer, and we need to figure out how, in addition to conditioning the host and the host immune compartment.”
Hegde remains hopeful that CAR-T will lead to better outcomes, at least for a subset of patients.
“[In 5 years], I think we will be using CAR T cells as combination therapies earlier in the disease course, in the setting of minimal residual disease or low disease burden,” she said.
‘Very nascent stage’
A phase 1 trial assessed CTX130 (CRISPR Therapeutics) — an investigational CD70-targeted allogeneic CAR T-cell therapy — for advanced clear cell renal cell carcinoma (RCC).
Eighty percent of treated patients exhibited disease control, and one patient had an ongoing complete response for 3 years as of data cutoff.
However, investigator Sumanta K. Pal, MD, FASCO, said he had hoped to see more tumor shrinkage among study participants.
The concept of mixed emotions perfectly characterizes where CAR T-cell therapies stand in solid tumors, Pal said.
“[CAR-T] in solid tumors is in a very nascent stage,” Pal, co-director of City of Hope’s kidney cancer program and a Healio | HemOnc Today Editorial Board member, said in an interview. “What we really demonstrate with CTX130 is that it is feasible to administer an allogeneic cell with CRISPR editing. We demonstrate that it’s safe. We saw very limited toxicity in the scope of our study, and we saw that there’s potential for durable responses, but we need to augment the spectrum of responses that we’re seeing.”
The COBALT-RCC study included 16 patients with clear cell RCC who had received at least one checkpoint or tyrosine kinase inhibitor.
A majority (81%) of patients achieved disease control, including 75% with stable disease.
“What we saw, which was quite unique, is that most patients had stabilization of their cancer,” Pal said. “That was the majority of the study, and that in and of itself is a laudable goal, but we were hoping to see tumor shrinkage in a greater portion of the population.”
Pal believes a combination approach could be applicable to other solid tumor types down the road.
“I think the future is exploiting multiple tumor antigens across the spectrum of tumor types,” he said. “It’s going to take a while for this field to evolve and, right now, we’re at a very preliminary stage. I think that seeing signals like we do [with] CTX130 is encouraging, but we do have to broaden the scope of response and, hopefully, we’ll see that this paradigm exists across other types, as well.”
Editor’s note: This article combines two previously published articles. To see the original pieces, click here and here.
- References:
- Bagley SJ, et al. Nat Med. 2024;doi:10.1038/s41591-024-02893-z.
- Chesney J, et al. J Immunoother Cancer. 2022;doi:10.1136/jitc-2022-005755,
- Choi BD, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2314390.
- Creelan BC, et al. Nat. Med. 2021;doi:10.1038/s41591-021-01462-y.
- Hegde M, et al. Nat Cancer. 2024;doi:10.1038/s43018-024-00749-6.
- NIH. First cancer TIL therapy gets FDA approval for advanced melanoma (press release). Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2024/fda-amtagvi-til-therapy-melanoma. Published March 5, 2024. Accessed March 26, 2024.
- Pal SK, et al. Cancer Discov. 2024;doi:10.1158/2159-8290.CD-24-0102.
- Preliminary clinical trial results show ‘dramatic and rapid’ regression after next generation CAR-T therapy (press release). Available at: https://www.massgeneral.org/news/press-release/clinical-trial-results-show-dramatic-regression-of-glioblastoma-after-next-generation-car-t-therapy. Published March 13, 2024. Accessed July 2, 2024.
- Rosenberg SA, et al. N Engl J Med. 1988;doi:10.1056/NEJM198812223192527.
- Srour SA, et al. Abstract CT002. Presented at: American Association for Cancer Research Annual Meeting; April 5-10, 2024; San Diego.
- For more information:
- Stephen J. Bagley, MD, MSCE, can be reached at sbagley@pennmedicine.upenn.edu.
- Meenakshi G. Hegde, MD, can be reached at mghegde@texaschildrens.org.
- Marcela V. Maus, MD, PhD, can be reached at mvmaus@mgh.harvard.edu.
- James J. Mulé, IPhD, can be reached at james.mule@moffitt.org.
- Sumanta K. Pal, MD, FASCO, can be reached at spal@coh.org.
- Steven A. Rosenberg, MD, PhD, FAACR, can be reached at sar@mail.nih.gov.
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