Benefits of novel CAR T-cell therapy ‘a big deal’ for patients with sarcoma
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Key takeaways:
- Half of the patients in the phase 1 trial had either a complete response or stable disease.
- The trial’s next iteration will investigate adding an immune checkpoint inhibitor.
A novel immunotherapy involving HER2-specific chimeric antigen receptor 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 a complete response or stable disease, including one boy with metastatic rhabdomyosarcoma, who enrolled twice and achieved a complete response both times — the second of which has persisted for 6 years.
Two patients experienced dose-limiting cytokine release syndrome, although the trial had strict safety guidelines, study investigators said.
“For a disease like this, especially in children, I think 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. Hedge, MD, associate professor in the department of pediatrics, section of hematology/oncology, at Baylor College of Medicine and Texas Children’s Hospital, told Healio. “While 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.”
‘We are stuck’
Sarcomas can be “complex” malignancies and patients often have poor prognosis, Hedge 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, but most of the potential targets in sarcomas are not restricted to the malignancy, Hedge explained.
“We have to make do with what has already shown some promise. HER2 is one of them,” she said.
“HER2, in most solid tumors, seems to correlate with poorer outcomes, whether it’s driving the cancer or not. Unlike HER2-amplifying breast cancer, HER2 is not really the driving genetic change or mutation in other solid cancers,” Hedge added. “However, in sarcoma and many other solid tumors, overexpression of HER2 has been correlated with poor clinical outcomes. 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.”
Hedge and colleagues initially investigated this approach in the HEROS study where patients received HER2-directed CAR-T cells.
Investigators 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,” Hedge said, adding they have not published long-term follow-up yet. “Three patients in the small cohort we tested who had the metastatic disease taken out after the CAR T-cell infusion had multiple recurrences back-to-back did not get any other therapy after that and stayed in remission for 10-plus years.”
The trial also produced a positive safety profile, Hege said, leading to the HEROS 2.0 study.
HEROS 2.0
Researchers enrolled individuals with HER2-expressing sarcoma who had recurrent or refractory disease after standard first-line therapy between March 18, 2015, and Sept. 25, 2019.
The trial had 13 patients and 14 enrollees (86% aged 17 years or younger; 64% male), as one participant reenrolled after recurrence. Fifty-seven percent of enrollees had a diagnosis of osteosarcoma. .
Additionally, 57% of patients had already received prior investigational treatment, 36% had between two to five surgeries to remove metastases and 50% previously had radiation, Hedge said.
“Radiation isn’t even standard for a lot of these patients,” she added.
The first grouping of patients received lymphodepletion with fludarabine, while the next two got fludarabine plus cyclophosphamide. Patients in the first HEROS trial did not receive lymphodepletion before CAR-T infusion.
Researchers evaluated safety as the study’s primary endpoint and antitumor activity as the secondary endpoint.
They observed a HER2 CAR-T expansion following 19 of 21 infusions.
Of the enrollees, 50% had a clinical benefit (21% complete response; 29% stable disease lasting up to 8.7 months), and the rest had progressive disease following the 6-week evaluation period.
The patient who reenrolled had two of the three complete responses, and 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,” Hedge said.
CRS 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, whereas two individuals — both in the final cohort — had grade 3 or 4, causing termination of enrollment in that group.
“We had very strict criteria for safety on this,” Hedge said.
Next steps and HEROS 3.0
Hedge believes understanding what works in cellular therapy comes down to three factors — the host, the tumor and the product itself.
Unfortunately for Hedge and other researchers investigating CAR-T in solid tumors, patient populations are often heterogeneous.
“I don't have enough just osteosarcomas to run any of these analyses meaningfully — to identify who these patients are — or enough rhabdomyosarcomas,” Hedge 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. 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.”
She added researchers need more tumors to study and noted the two adults in the study became a useful part of HEROS 2.0.
“There are a lot of ethical challenges in getting tumor tissues from children after the treatment ... because if they are going to a surgical procedure that’s not clinically indicated, then you’re putting them at risk,” Hedge said. “In this study, we made every effort to try to get tumors from these patients when they’re going through clinically indicated procedures, and I think it paid off in the end because we were able to study a good chunk of tumors from these patients to identify some trends in what happens in the tumor microenvironment.”
As for this CAR-T product, Hedge 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 the CAR T cells. This probably involves designing the CAR T cells differently, introducing more modifications to the CAR T cells that can be activated within the tumor, but also prepping the tumor with other agents.”
Researchers plan on evaluating this theory using an anti-PD-1 antibody in HEROS 3.0, Hedge said — a study they are currently recruiting for.
She remains hopeful patients have a better tomorrow ahead.
“I think we will achieve better outcomes, at least in a subset of patients,” Hedge said. “[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.”
For more information:
Meenakshi G. Hedge, MD, can be reached at mghegde@texaschildrens.org.
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