Early findings suggest CAR-T for solid tumors may advance beyond ‘very nascent stage’
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It’s only the beginning.
That common refrain echoed throughout the oncology community in February when the FDA approved lifileucel (Amtagvi, Iovance Biotherapeutics) — a tumor-derived autologous T-cell immunotherapy — for treatment of adults with unresectable or metastatic melanoma.
Source: Massachusetts General Hospital Cancer Center
Several decades of research laid the groundwork for the approval of lifileucel — the first cellular therapy indicated in the United States for solid tumors — but leaders in the field have been quick to emphasize they consider it a major first step, not a culmination.
That optimism remains pervasive among investigators exploring whether chimeric antigen receptor T-cell therapy — only approved in the U.S. for hematologic malignancies — can provide transformative benefits for malignancies beyond blood cancers.
Results of several studies released in the past few months — focused on use of CAR-T for brain tumors, sarcoma and kidney cancer — suggest the answer may indeed be yes.
Healio 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 CAR-T for solid tumors.
‘Dramatic and rapid’ response
A novel CAR T-cell therapy induced significant tumor reductions among patients with glioblastoma, results of a phase 1 trial published in The New England Journal of Medicine showed.
All three patients treated with CARv3-TEAM-E T cells experienced “dramatic and rapid response,” investigator Elizabeth Gerstner, MD, neuro-oncologist in the department of neurology at Massachusetts General Hospital, said in a press release.
The results emerged from a safety run-in cohort, where researchers administered a single dose of CARv3-TEAM-E cells (CAR-TEAM) and monitored patients for toxicity.
“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 | HemOnc Today Associate Medical Editor, told Healio | HemOnc Today.
“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, especially without any steroids or bevacizumab or any other reason to expect that the imaging might change at all.”
All three adults in the INCIPIENT trial had received radiation and chemotherapy for grade 4, recurrent EGFRvIII-positive glioblastoma.
One patient — a 74-year-old man — exhibited rapid tumor reduction 1 day after infusion. This continued for 2 weeks but did not last. He received a second dose and, at multiple points of his treatment, his EGFRvIII and EGFR copy numbers became almost undetectable.
The second patient — a 72-year-old man — exhibited an 18.5% tumor reduction 2 days after treatment. This rose to 60.7% after 69 days, and his response lasted more than 150 days.
The third patient — a 57-year-old woman — exhibited near-complete tumor regression by 5 days after treatment. She developed disease recurrence at 1 month.
No effective treatments exist for glioblastoma, but CAR-T can be an effective approach, Maus said.
“Unlike small molecules or protein therapeutics, which can only passively diffuse into tissues and have a particularly hard time getting past the blood-brain barrier, T cells are living drugs that can actively migrate into tissues,” Maus said. “Natural immune responses are also not very efficient when it comes to the brain. It is an immune-privileged site. CAR T cells can theoretically overcome several of these 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. We had evidence of this from mouse models, but this is our first in-human experience.”
One of the patients developed grade 3 encephalopathy and another developed grade 3 fatigue.
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.”
‘We were shocked’
A novel bivalent-targeting, intrathecally delivered CAR T-cell therapy exhibited activity in recurrent glioblastoma, according to findings published in Nature Medicine.
All six patients achieved tumor reduction within 2 days of receiving the CAR-T.
Despite the positive signals, no patients treated achieved an objective radiographic response based on study criteria.
“These results exceeded our expectations,” Stephen J. Bagley, MD, MSCE, section chief of neuro-oncology at Penn Medicine, told Healio | HemOnc Today. “We’ve done two trials previously and we didn’t see tumors shrink in any of the patients. Here, the first patient we treated [had] an MRI scan 24 hours after the injection because [they experienced] neurotoxicity. The MRI was actually obtained for safety monitoring reasons, and we were shocked to see that the tumor had almost completely regressed in 24 hours.”
The novel CAR-T targets EGFR and interleukin-13 receptor alpha-2 (IL13Ra2) tumor-associated antigens.
In previous trials, Bagley and colleagues used CAR-T to target EGFRvIII.
“One of the key reasons we think [the trials did not work] was antigen escape,” Bagley said. “In our first trial, we were able to compare pre- vs. post-CAR T cell tumor tissue [from] all seven patients. In all cases, EGFRvIII expression went down [after] CAR-T, indicating that we had reduced the tumor that was expressing that antigen, but EGFR amplification levels actually stayed the same or went up in some cases. We were kind of reducing target, but the tumor was still growing out antigen-negative cells.”
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 a phase 1 trial, researchers tested the CAR-T on six adults with recurrent, isocitrate dehydrogenase wild-type glioblastoma with EGFR amplification.
In prior trials, researchers administered CAR-T via IV. This time, they did so intrathecally, directly into the spinal fluid.
“When we delivered CAR T cells into the blood, we’ve showed that some of those cells do actually make their way from the blood into the brain tissue, but it’s probably just a subset of the cells,” Bagley said. “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.”
The dual-targeting and a new delivery system produced rapid results.
One patient maintained tumor regression for 33 days. A second had 2 months of stable disease before dying of hydrocephalus. A third remained in response for 7 months at data cutoff, a fourth had 3 months of tumor stability, and two others had a month of tumor stability at the time of data cutoff.
“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.”
Every participant developed immune effector cell-associated neurotoxicity syndrome (ICANS), although researchers had to create an adapted ICANS grading system because patients with glioblastoma can already have issues such as speech problems and motor deficits.
Researchers did not observe any grade 4 or grade 5 toxicities. Grade 3 adverse events included fatigue, decreased lymphocyte count, CAR neurotoxicity, skin ulceration, anorexia, muscle weakness and hypoxia. Neurotoxicity was manageable and reversible in all cases, Bagley said.
Trial protocol has approval for 18 participants. Researchers hope to get more answers on response durability and how that affects OS, as well as why the CAR-T works better in some patients more than others.
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. “Their clinical condition isn’t as good. They’re often more symptomatic. Time is of the essence, and there’s a lot to do in these CAR-T studies. You have to collect the cells by leukapheresis, manufacture the cells and administer them. If we were able to do all of that earlier in the disease course, when things are not as urgent for the patient and the patient is in better clinical condition, I think there’s a higher likelihood for long-term success.”
‘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 | HemOnc Today. “[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 sarcoma and many other solid tumors, overexpression of HER2 has been correlated with poor clinical outcomes,” Hegde said. “It’s possible that it has some role in the tumor cell surviving or metastasizing ... and we just haven’t understood the exact mechanism, even though it is not the initiating force.”
Hegde and colleagues initially investigated HER2-directed CAR T cells in the HEROS study. Researchers detected the CAR-T shortly after infusion, but it became undetectable within a few weeks.
“Though we did not have any complete responses in that cohort, we did find some evidence of activity,” Hegde said.
In HEROS 2.0, researchers enrolled individuals with HER2-expressing sarcoma who had recurrent or refractory disease after standard first-line therapy.
The trial included 13 patients (86% aged 17 years or younger; 64% male).
Fifty-seven percent of enrollees had osteosarcoma.
More than half (57%) had received prior investigational treatment, 36% had two to five surgeries to remove metastases, and 50% previously had radiation.
The first grouping of patients received lymphodepletion with fludarabine, and the next two got fludarabine plus cyclophosphamide.
Safety served as the primary endpoint and antitumor activity served as a secondary endpoint.
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.
One boy with metastatic rhabdomyosarcoma enrolled twice and achieved a complete response both times, the second of which has persisted for 6 years. A 16-year-old girl with osteosarcoma had tumor remission for 42 months until relapse.
“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. Of the patients who had CRS, nine had grade 1 or 2 cases. Two individuals — both in the final cohort — had grade 3 or grade 4 CRS, causing termination of enrollment in that group.
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.
“If you were able to do this treatment a little bit earlier, you would have more patients who would have clinically indicated surgery that they would go through,” Hegde added. “But, in this cohort, for example, most patients who could have surgery already had it multiple times. It becomes very challenging to really understand why treatment works and why treatment doesn't work.”
Hegde believes 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. We have to figure out how to make the tumors more susceptible to CAR T cells. This probably involves designing CAR T cells differently, introducing more modifications to CAR T cells that can be activated within the tumor, but also prepping the tumor with other agents.”
Researchers plan to evaluate this theory in HEROS 3.0. That trial, for which recruitment is open, will incorporate an anti-PD-1 antibody.
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.”
Roughly 30% of patients with clear cell RCC develop metastases that require therapy. Standard care includes immune checkpoint inhibitors alone or in combination with vascular endothelial growth factor (VEGF)-directed therapy.
Response rates range from 42% to 71%, but few patients achieve complete response. Secondary treatments have limited efficacy. Salvage treatment with VEGF-directed therapy has conferred median PFS of 5 to 8 months, with response rates between 28% and 43%.
“After a patient has exhausted VEGF pathway-directed therapies, we do really have to get creative,” Pal said. “That’s where I think these clinical trials come into play.”
Prior studies showed CD70 — which appears to limit T-cell expansion to fight tumors — had been found in 58% of lymphomas, 43% of solid tumors and 80% of clear cell RCC samples.
“CD70 is a very pervasive antigen in kidney cancer, so it’s one that I think is always amenable to therapeutic targeting,” Pal said.
Other studies tried to target CD70 in various ways — including with antibody-drug conjugates, bispecific T-cell engagers and monoclonal antibodies — but with limited success.
Pal and colleagues aimed for improved results with CTX130, using CRISPR-Cas9 gene editing to insert an anti-CD70 CAR expression cassette.
The COBALT-RCC study included 16 patients (median age, 63 years; 87.5% men; 100% stage IV at enrollment) with clear cell RCC who had received at least one checkpoint or tyrosine kinase inhibitor.
Study participants received lymphodepletion prior to CAR-T infusion, and they received various dose levels and numbers of infusions of CTX130.
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.”
One patient achieved complete response that has lasted for 3 years.
“This patient had progressed beyond targeted therapy, checkpoint inhibitors and now has complete remission of this cancer,” Pal said.
Pal described the safety profile for CTX130 as “promising” and “unique,” given that no cases of ICANS and no reports of grade 3 or higher CRS occurred.
Fifty percent of study participants experienced grade 1 or grade 2 CRS, 25% had serious treatment-related adverse events — all CRS — and no patient developed graft-versus-host disease.
CTX130 could be detected in the bloodstream 20 minutes after infusion, declined around day 2 or 3, had an expansion and peak around day 7 to 15, and then decreased to undetectability at day 28.
Pal and colleagues are conducting a phase 1/phase 2 trial of a next-generation cellular therapy — CTX131 — which has been edited to improve the durability of the T cell.
“There’s two edits [in CTX 131] that are actually specifically intended to increase the durability of the T cell in the bloodstream,” Pal said. “By making these two edits and other portions of the cell, I think that we can increase the T-cell persistence.”
Pal believes the 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.”
References:
- Bagley SJ, et al. Nat Med. 2024;doi:10.1038/s41591-024-02893-z.
- Choi BD, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2314390.
- Hegde M, et al. Nat Cancer. 2024;doi:10.1038/s43018-024-00749-6.
- 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 22, 2024.
- 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.
Sumanta K. Pal, MD, FASCO, can be reached at spal@coh.org.
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