Novel immunotherapy creates ‘cancer-fighting cells,’ shrinks colon cancer tumors
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Key takeaways:
- A novel cellular immunotherapy shrank tumors among some patients with metastatic colon cancer.
- The approach could be applied to other solid, epithelial cancers.
A novel immunotherapy approach for solid, epithelial cancers reduced tumor burden among multiple patients with metastatic colon cancer, according to phase 2 study results.
The treatment induced tumor regression in the liver, lungs and lymph nodes, and it prevented regrowth for as long as 7 months.
“We use an individual’s T-cell receptors to convert normal cells into cancer killers,” 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. “This kind of use of a living drug — the patient’s own lymphocytes to treat the patient — is probably the most exciting area in modern oncology.”
Background
Chimeric antigen receptor T-cell therapy has extended survival for individuals with hematologic malignancies, and tumor-infiltrating lymphocytes (TILs) improve outcomes for some people with melanoma.
However, no cellular therapies have been proven effective for treatment of other solid tumors, such as colon, pancreatic or stomach cancers.
“Solid, epithelial cancers represent 90% of all patients who die of cancer because once they develop metastatic disease, you can beat it back with chemotherapies but you cannot cure it,” Rosenberg said. “Ultimately, the chemotherapies stop working, and the death rate is near 100% once the cancer spreads.”
TILs work in melanoma because of the large number of mutations, Rosenberg said. Solid cancers have far fewer abnormalities.
“We can identify TILs that will recognize a cancer in in vitro assays from 70% to 80% of all patients with colon cancer,” he added. “The problem is, when you give those TILs — the way we do it in melanoma — they do not cause cancer regression. There are a variety of reasons. For one, those TILs are highly differentiated. They’re senescent. They’ve lost a lot of their ability to divide in the patient.”
Making ‘cancer-fighting cells’
TILs still provide valuable information, though, which Rosenberg and colleagues used to develop a new immunotherapy. They took the gene-encoding receptor that identified the cancer in a TIL and inserted it into the patient’s normal lymphocytes using a retrovirus.
“The TILs that we identify are very rare — 1 in 1,000 to 1 in 100,000,” Rosenberg said. “But, because we can actually take that receptor and put it into normal lymphocytes, we can make as many cancer-fighting cells as we want by converting normal lymphocytes into lymphocytes that can recognize the cancer.”
Rosenberg described the process as “analogous” to CAR-T production.
“You take a CAR receptor that recognizes a lymphoma — the CD19 molecule — put it in a normal cell and use them for therapy,” he said. “We’ve figured out a way now to make a cell that recognizes a neoantigen that is present on the cancer uniquely and not on normal cells.”
Researchers tested the therapy in seven patients with metastatic, refractory, mismatch repair-proficient colorectal cancer. Each individual had at least two prior rounds of chemotherapy.
Participants received lymphodepletion prior to treatment, several doses of pembrolizumab (Keytruda, Merck) — the first occurring before therapy — and interleukin-2 following cell infusion.
Results
Three of the seven treated individuals achieved partial response, resulting in tumor regression in the liver, lung and lymph nodes.
Researchers reported median PFS of 4.6 months, with the three responders remaining progression free for 4, 6 and 7 months.
“This is the first proof of principle that you can target these neoantigens, these unique antigens on the solid cancers that are unique to each individual patient,” Rosenberg said.
All patients experienced grade 3 or grade 4 cytopenias. One developed grade 4 cytokine release syndrome, which clinicians resolved. One developed transient acute bleeding diathesis.
Rosenberg called the therapy “well tolerated” and said it had a similar safety profile as TILs.
‘This can be improved’
The results are encouraging but more work must be done, Rosenberg said.
“We’ve shown that this can work, and now we have to make it work better,” he said.
Rosenberg discussed how he and colleagues first described TILs in melanoma in 1988, but the FDA only approved the treatment this year.
“It required a lot of modifications,” he said. “We know a lot more now about immunology and the immune reaction against cancers. I have every expectation that this can be improved.”
Rosenberg believes one way to improve the immunotherapy is inserting the receptor into specific subpopulations of lymphocytes. Additionally, the lymphocytes could be given with a vaccine that targets the same neoantigen.
The research team is focused on improving durability and examining why the treatment worked for some patients but not others.
They also are investigating T-cell receptors themselves.
“Recognizing the tumor in vitro — in the laboratory — is one thing, but getting it to recognize strongly enough in the patient is a problem,” Rosenberg said. “We’re looking at the characteristics of the T-cell receptors that we transfer to figure out what makes a good T-cell receptor that will cause regression in the patient.”
Rosenberg said he is “excited” about the future of the treatment.
“[The best-case scenario] is it will extend the ability to treat patients right now,” Rosenberg said. “TILs do not work in the solid cancers. CAR T cells do not work in the solid cancers. So we’re left with chemotherapy, which can help patients but is rarely curative once the tumor has spread. These lymphocytes can recognize tumors from the breast, from the pancreas, and from many other solid cancers. Thus, with further development, this approach could potentially be applied to many other cancer types.”
For more information:
Steven A. Rosenberg, MD, PhD, can be reached at sar@mail.nih.gov.
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