Emerging Allogeneic CAR T Candidates Usher in a New Era

Dose-dependent engraftment of the investigative CAR T-cell therapy CYAD-211 was demonstrated in the first patient with relapsed/refractory multiple myeloma to receive this dose in the phase 1 IMMUNICY-1 trial, and no graft-versus-host disease has been reported to date.

Dose-dependent engraftment up to 300 × 106 cells per infusion (dose level 3) of the investigative CAR T-cell therapy CYAD-211 was demonstrated in the first patient with relapsed/refractory multiple myeloma to receive this dose in the phase 1 IMMUNICY-1 trial (NCT04613557), and no graft-versus-host disease (GVHD) has been reported to date.1

CYAD-211 is a first-in-class, non-gene edited allogeneic anti-BCMA CAR T-cell product that uses an “all-in-one” vector approach to co-express a single optimized short hairpin RNA (shRNA) to downregulate the expression of the T-cell receptor (TCR) CD3ζ subunit along with the CAR.

According to Celyad Oncology SA, the manufacturer of CYAD-211, non–gene editing technology reduces the risk of GVHD, but does not permanently alter the genome integrity, thus decreasing the potential safety risk associated with off-target genome modifications.

“We are ushering in a new era of allogeneic CAR-T candidates using novel technological advances, including our proprietary shRNA platform for allogeneic CAR T production and now the addition of our ‘armored’ CAR capabilities with co-expression of the cytokine interleukin [IL]-18,” Filippo Petti, chief executive officer of Celyad, stated in a press release. “We believe the advances we’re making may address many of the current modality limitations and have the potential to provide real-world benefits for patients, including more accessible CAR T-cell treatment options, if approved.”

Investigators are assessing the safety, clinical activity, and cell kinetics of CYAD-211 following 3 consecutive days of preconditioning with 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine in patients with multiple myeloma.

Patients needed to have received at least 2 prior therapies, including exposure to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) either alone or in combination. Patients also needed to have at least 1 complete cycle of treatment for each prior regimen, achieved at least 1 response to a prior regimen, and had measurable disease per International Myeloma Working Group Response Criteria.

Preliminary data from the trial were presented during the 2021 EHA Virtual Congress.1,2 At the time of the presentation, 6 patients received 30 × 106 cells per infusion (dose level 1) or 100 × 106 cells per infusion (dose level 2) of the product.

Five patients were determined to be evaluable for efficacy. Of these patients, 2 had confirmed partial responses (PRs) to treatment and 3 others achieved stable disease. Both patients who experienced the PR were triple-exposed, having received an IMiD, a PI, and an CD38-targeted antibody, with a bone marrow plasma cells infiltration of 15% at baseline.

Moreover, CYAD-211 cells were detected by PCR-based methods in the peripheral blood of all 6 patients. However, the signals in 2 patients were noted to be low and just above the limit of detection. Cell engraftment was seen in all 3 patients who received dose level 2 of the therapy at a similar magnitude. All patients in the dose level 2 cohort showed deep lymphodepletion. Across dose level 1, the duration and depth of lymphodepletion appeared to be variable, which could explain the differences in engraftment reported.

No dose-limiting toxicity (DLT) or CAR T-cell–related encephalopathy syndrome was observed. Moreover, no grade 3 or higher treatment-related adverse effects were reported with the therapy. No immune effector cell–associated neurotoxicity syndrome nor GVHD was experienced. One patient with PR experienced grade 1 cytokine release syndrome.

Enrollment for IMMUNICY-1 is ongoing and Celyad announced plans to explore higher preconditioning regimen doses for future cohorts. The company expects to release further data later this year.

CYAD-101 to Proceed to Phase 1b Testing

In January 2021, phase 1 data on 15 patients enrolled to the alloSHRINK trial (NCT03692429) were reported. The trial assessed the safety, cell kinetics, and clinical activity of CYAD-101, an allogeneic NKG2D-receptor and TCR inhibitory molecule (TIM)–based, non-gene edited CAR T candidate that was administered concurrently with FOLFOX in the treatment of patients with relapsed/refractory metastatic colorectal cancer (mCRC).

Patients who progressed following prior treatment with oxaliplatin- or irinotecan-based chemotherapies were treated at 1 × 108, 3 × 108, 1 × 109 cells per infusion administered concurrently with FOLFOX as preconditioning chemotherapy in the dose-escalation segment of the trial. Eight (53.3%) patients experienced tumor burden decrease; this included 6 patients who were treated at the 1 × 109 dose level. Moreover, 2 (13.3%) patients achieved a PR and 9 had stable disease; 7 of these patients were stable for at least 3 months.3,4

Investigators observed no DLTs or GVHD in this population. The company shared plans to initiate the phase 1b KEYNOTE-B79 trial of CYAD-101 following FOLFOX plus pembrolizumab (Keytruda) in the treatment of patients with refractory mCRC with microsatellite stable/mismatch repair–proficient disease in partnership with Merck later this year.1

CYAD-203 Under Exploration for Solid Tumors

CYAD-203 is a CAR T product that was engineered to co-express the cytokine IL-18 with the NKG2D CAR receptor.1 A proinflammatory cytokine that directly potentiates the anticancer activity achieved with CAR T cells, IL-18 also alters the balance of pro- and anti-inflammatory cells within tumor tissue.

The product is on track to be the first IL-18–secreting allogeneic CAR T candidate, according to Celyad, and investigational new drug (IND)–enabling studies are ongoing.

The submission of an IND application for the product’s use in patients with solid tumors is anticipated in mid-2022.

References

  1. Celyad Oncology presents updates on allogeneic CAR T clinical candidates and shRNA-based preclinical concepts at Research & Development Day. News release. Celyad Oncology SA. July 20, 2021. Accessed July 22, 2021. https://bit.ly/3kKzZWt
  2. Anguille S, Al-Homsi AS, Deeren D, et al. Objective response at low dose in the first-in-human IMMUNICY-1 trial evaluating non-gene edited allogeneic CYAD-211 anti-BCMA CAR-t product in relapsed or refractory multiple myeloma. Presented at: 2021 EHA Virtual Congress; June 9-17, 2021; Virtual. Abstract EP739. https://bit.ly/3y38ISX
  3. Prenen H, Dekervel, J, Anguille S, et al. CYAD-101: An innovative non-gene edited allogeneic CAR-T for solid tumor cancer therapy. J Clin Oncol. 2020;38( suppl 15):3032-3032. doi:10.1200/JCO.2020.38.15_suppl.3032
  4. Celyad Oncology presents data update from phase 1 alloSHRINK trial for CYAD-101 in mCRC at ASCO-GI Symposium. News release. Celyad Oncology SA. January 18, 2021. Accessed July 22, 2021. https://bit.ly/3hZSJzD