On November 11, 2019 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell therapies, reported highlights from the company’s NKG2D-based CAR-T clinical candidates for the treatment of metastatic colorectal cancer (mCRC), including its novel, off-the-shelf cell therapy CYAD-101 and alloSHRINK dose-escalation Phase 1 trial (Press release, Celyad, NOV 11, 2019, View Source [SID1234550849]). Results were presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 34th Annual Meeting, held in Washington D.C. from November 6-10, 2019.
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Dr. Frédéric Lehmann, VP of Clinical Development & Medical Affairs at Celyad, commented, "We are encouraged by the latest results from the alloSHRINK trial in metastatic colorectal cancer patients previously exposed to oxaliplatin- and irinotecan-based chemotherapies, including the tolerability profile and early antitumor activity of CYAD-101 with prior FOLFOX preconditioning chemotherapy. In particular, the lack of clinical and laboratory evidence of graft-versus-host-disease for CYAD-101, which incorporates our proprietary T-cell receptor inhibitory molecule to reduce signaling of the TCR complex, establishes proof-of-concept for this industry-leading, off-the-shelf CAR-T approach. In addition, any host-versus-graft reaction against the allogeneic CAR-T product candidate appears to be controlled by the non-myeloablative FOLFOX chemotherapy. Overall, these encouraging data from the alloSHRINK trial warrant further evaluation of CYAD-101."
Filippo Petti, CEO of Celyad, stated, "Treatment of advanced metastatic colorectal cancer patients beyond the second line of metastatic chemotherapy remains a high unmet medical need. Our confidence in CYAD-101 has continued to build as data from the alloSHRINK trial have emerged over the past year. We look forward to the planned expansion segment of the alloSHRINK trial to further evaluate the CAR-T product candidate for refractory mCRC patients as we continue to execute on the company’s vision for the treatment of patients with advanced solid tumors with allogeneic CAR-T therapies."
alloSHRINK Phase 1 Trial Update
Safety and Tolerability
To date, a total of 12 patients with relapsed/refractory mCRC who progressed after previous treatment with oxaliplatin or irinotecan have been enrolled in the ongoing dose-escalation Phase 1 alloSHRINK trial evaluating three consecutive dose levels of CYAD-101 administered concurrently with FOLFOX chemotherapy. The number of prior therapies received by patients enrolled in the trial ranged from one to six with a mean of three.
No clinical evidence of graft-versus-host disease (GvHD) has been observed following 35 injections of CYAD-101. These data continue to support the ability of the company’s novel inhibitory peptide T cell receptor (TCR) inhibiting molecule (TIM) to reduce signaling of the TCR complex through a non-gene edited approach.
Treatment with CYAD-101 in association with FOLFOX chemotherapy was well-tolerated, with no report of dose-limiting toxicity. Six of 12 patients enrolled in the trial reported at least one treatment-related adverse event (AE), however all AEs reported were grade 1 or 2 including one patient who experienced cytokine-release syndrome (grade 1). No patient discontinued treatment due to AEs.
Clinical Activity
Encouraging anti-tumor activity was observed in the trial with two patients who achieved a confirmed partial response (PR) according to RECIST 1.1 criteria and five patients achieved stable disease (SD) of more than or equal to three months of duration. Tumor burden decrease was observed in six out of 12 patients in total.
Cell Kinetics
Host-versus-graft (HvG) reaction against the allogeneic CYAD-101 cells appears to be controlled by the non-myeloablative FOLFOX chemotherapy as evidenced by similar levels of CYAD-101 cell engraftment following the second and third infusions of the allogeneic cell product candidate.
Following administration of FOLFOX chemotherapy, CYAD-101 cells demonstrate similar kinetics as the autologous NKG2D-based CAR-T therapy CYAD-01 as evaluated in the Phase 1 SHRINK trial.
Next Steps
An additional three patients have been enrolled at dose level three (one billion cells per infusion) of the trial for a total of nine patients in the cohort, as planned per protocol. Preliminary results from the completed dose-escalation segment of the alloSHRINK trial are expected in first half 2020.
Based on the encouraging data observed to date for the Phase 1 alloSHRINK trial, the Company plans to expand the trial to further evaluate CYAD-101 with prior FOLFOX chemotherapy in refractory mCRC patients. Enrollment in the expansion segment of the trial is expected to begin in mid-2020 following the production of additional CYAD-101 cells planned during first half 2020.
About CYAD-101 and alloSHRINK Trial
CYAD-101 is an investigational, non-gene edited, allogeneic (healthy donor derived) CAR-T therapy engineered to co-express a chimeric antigen receptor (CAR) based on NKG2D, a receptor expressed on natural killer (NK) cells that binds to eight stress-induced ligands and the novel inhibitory peptide TIM (T cell receptor [TCR] Inhibitory Molecule). The expression of TIM reduces signalling of the TCR complex, which is responsible for GvHD.
alloSHRINK is an open-label, dose-escalation Phase 1 trial assessing the safety and clinical activity of three consecutive administration of CYAD-101 every two weeks administered concurrently with FOLFOX (combination of 5-fluorouracil, leucovorin and oxaliplatin) chemotherapy in patients with refractory mCRC.
About Colorectal Cancer
Colorectal cancer is the third most common type of cancer among both men and women worldwide and is the fourth in terms of mortality. In 2018, approximately 1.8 million people were diagnosed with colorectal cancer with about 140,000 and 500,000 diagnoses in the United States and Europe, respectively. According to data from the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), approximately 40% of patients are diagnosed with early-stage, localized-stage disease. The five-year survival rate of localized disease is approximately 90%. In patients where the cancer has spread to distant parts of the body, as in metastatic colorectal cancer, the five-year survival rate drops to approximately 15%.