CYAD-01 — Celyad‘s CAR T-cell product — is showing promise as a treatment for metastatic colorectal cancer patients (mCRC), both alone and in combination with standard of care chemotherapy, according to findings from two clinical trials.
These results were recently presented at the Society for Immunotherapy of Cancer (SITC) 33rd Annual Meeting in Washington, D.C., in the poster, “Results and perspectives from Phase 1 studies assessing the safety and clinical activity of multiple doses of a NKG2D-based CAR-T therapy, CYAD-01, in metastatic solid tumors.”
“We are excited about the progress we have made thus far with our solid tumor program for lead candidate CYAD-01,” David Gilham, PhD, vice president of research and development at Celyad, said in a press release. “We continue to investigate complementary regimens for CYAD-01 for the treatment of metastatic colorectal cancer that we believe may help to drive additional clinical activity in this devastating disease where a true unmet medical need exists.”
CYAD-01 is an investigational CAR T-cell treatment, in which patients’ own T-cells are harvested and engineered to produce a chimeric receptor — called NKG2D — that recognizes multiple tumor proteins. It is an approach of relevance to nearly 80 percent of all cancers, and is now under testing in open-label Phase 1 trials in different cancers.
THINK (NCT03018405) is evaluating CYAD-01 in seven types of refractory (treatment resistant) cancers, including five solid tumors (colorectal, ovarian, bladder, triple-negative breast, and pancreatic cancers) and in two blood cancers (acute myeloid leukemia and multiple myeloma).
The trial is testing three CYAD-01 doses — 300 million, 1 billion and 3 billion cells per injection — with patients given three treatment doses within two weeks. Those receiving the highest dose level that shows activity — achieving stable disease or better — are eligible for another three CYAD-01 injections.
To date, it has included 14 patients — 11 with mCRC, two with ovarian cancer, and one with pancreatic cancer — who failed to respond to prior treatments. Among them, four (29%) experienced stable disease: three mCRC patients and one with ovarian cancer.
Disease stabilization was observed across all three dose levels, and two mCRC patients assigned the highest dose had stable disease for a minimum of four months, data showed.
Nine serious or life-threatening side effects were reported in five patients. One person receiving the highest dose also developed a life-threatening cytokine release syndrome (CRS) — a common side effect of CAR T-cell treatments caused by an overactive immune system — but the other five treated with this dose had no evidence of severe toxicity.
In February, the trial was amended to include an additional cohort — called THINK CyFlu – where patients would receive the standard preconditioning chemotherapy — cyclophosphamide and fludarabine, or CyFlu — to deplete their white blood cells and create room for the CAR T-cells to expand.
In this group, two treated patients have experienced no serious adverse events to date. These patients are not yet ready to be evaluated for a clinical response, but preliminary data suggests that preconditioning treatment with CyFlu improves the expansion of CYAD-01 cells.
The SHRINK (NCT03310008) study is testing increasing doses of CYAD-01, given along with standard chemotherapy (called FOLFOX), in colorectal cancer patients whose liver metastasis may be removed by surgery.
As of October, the trial included three mCRC patients never treated for their metastatic disease, and each was given the lowest dose level. All three benefitted from the combination, with one patient showing a complete tumor response and the two others partial responses.
“Initial activity of concurrent treatment of CYAD-01 with FOLFOX builds upon disease stabilization seen with standalone CYAD-01,” the researchers said.
The combination was also well-tolerated, without a greater number of adverse events compared to chemotherapy, and no patients experiencing a serious adverse event. Full data from SHRINK is expected by mid-2019.
The third trial, called LINK (NCT03370198), aimed to assess ascending doses of CYAD-01 in colorectal cancer patients with liver metastases that could not be removed by surgery. But the trial only recruited one patient, and the company decided to stop patient enrollment.
“I am encouraged that to date CYAD-01 is well tolerated as a monotherapy for the treatment of mCRC, while preliminary observations of clinical activity in the form of disease stabilization imply that there is potential for the approach,” said Frédéric Lehmann, MD, vice president of clinical development and medical affairs at Celyad. “[T]he initial findings of clinical activity reported from the initial dose level of CYAD-01 when administered concurrently with standard-of-care chemotherapy in the SHRINK trial are encouraging and provide support for this view.”
Celyad is also developing CYAD-101, a donor-derived CAR T-cell therapy based on CYAD-01, and plans to soon evaluate its potential in treating patients with colorectal cancer that cannot be surgically removed.
A first Phase 1 trial, called Allo-SHRINK (NCT03692429), is expected to begin enrolling patients this year.
