Emerging Allogeneic CAR T Candidates Usher in a New Era

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