Developmental Interest in Allogeneic Placenta–Derived Cell Therapies Expands

Cellular medicine could represent the next frontier in the treatment of patients with cancer and many other diseases with a high unmet need. Although progress made with approaches like CAR T-cell therapies have served to advance the field forward, opportunities exist for further innovation.

After closing a merger with GX Acquisition Corp., Celularity Inc., a clinical-stage cellular medicine company, is taking the next step in its evolution to enable further development of novel, off-the-shelf allogeneic placenta–derived cellular therapies.¹

“Celularity aims to transform the way we approach the treatment of cancer and other diseases by harnessing the versatility, unique immune biology, and innate stemness of placental-derived cells,” Robert J. Hariri, MD, PhD, found, chairperson, and chief executive officer of Celularity, stated in a press release. “We are immensely proud of our clinical development results so far as well as the state-of-the-art manufacturing capabilities we built to support rapid scaling and a competitive cost structure for our placental-derived cell therapeutics. We believe off-the-shelf, allogeneic cell therapies will drive a paradigm shift in how clinicians approach the treatment of cancer and other serious diseases.”

CYNK-001, the company’s lead product candidate, is the only cryopreserved, allogeneic, off-the-shelf natural killer (NK) cell therapy to be developed from placental hematopoietic stem cells. The agent expresses perforin and granzyme B, has showcased cytotoxic activity against hematological tumors and solid tumor cell lines, and can secrete immunomodulatory cytokines in the presence of tumor cells.

The novel therapy is under investigation as a potential option in multiple myeloma, acute myeloid leukemia (AML), and glioblastoma multiforme; it is also being evaluated in infectious diseases like COVID-19 (NCT04365101).

An ongoing, open-label, multi-dose, phase 1 trial (NCT04310592) is examining the maximum-tolerated dose (MTD) or maximum planned dose of CYNK-001 in an estimated 22 patients with acute myeloid leukemia (AML).² To participate, patients need to have primary or secondary AML and be in first or second morphological clinical response (CR), morphological CR with incomplete hematologic recovery, or a morphologic leukemia-free state per European LeukemiaNet recommendations for AML Response Criteria.

Patients also need to have MRD positivity, be aged between 18 and 80 years old, have an ECOG performance status of 0 to 2, and be able to be off immunosuppressive therapy for at least 3 days before infusion with the therapy. Patients who previously had central nervous system involvement are allowed to enroll if they had been treated and their cerebral spinal fluid is clear for at least 2 weeks before undergoing lymphodepletion.

Exclusion criteria include significant medical conditions, laboratory abnormalities, bi-phenotypic acute leukemia, acute promyelocytic leukemia, unacceptable organ function, autoimmune disease, uncontrolled graft-vs-host disease (GVHD), and GVHD that requires corticosteroids.

Participants are first given cyclophosphamide plus fludarabine. Then, they are administered CYNK-001 at 3 varying dose levels—1.8 billion, 3.6 billion, and 5.4 billion CYNK-001 cells—on days 0, 7, and 14. The primary objectives of the research include dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and frequency and severity of adverse effects. Important secondary objectives include the number of patients who convert from MRD-positive to -negative status; time to, and duration of, MRD response; progression-free survival; time to progression; duration of morphologic complete remission; and overall survival.

In June 2021, the study was expanded to include patients with relapsed/refractory AML following a case of conversion to MRD negativity, when the therapy was delivered at its highest dose level.³

The decision to expand the trial followed observations of a patient with NPM-1–positive, FLT3-negative AML and good-risk cytogenetics who had been administered 5.4 billion CYNK-001 cells. The patient converted from MRD-positive to -negative status, without experiencing any DLTs.

For this patient, primary induction treatment with 7+3 chemotherapy had failed, and so they had gone on to receive second induction therapy followed by high-dose cytarabine consolidation. At this time point, the patient achieved a complete CR, but MRD was found to be persistent; it did not clear following 4 months of treatment with azacitidine. MRD positivity was confirmed on a marrow biopsy.

The patient went on to enter the phase 1 trial, where they received lymphodepletion, and then received 1.8 billion CYNK-001 cells on days 0, 7, and 14 in the outpatient setting, which totaled to 5.4 billion CYNK-001 cells. On day 28, the patient had converted from MRD positivity to negativity. CYNK-001 cells were present in both the peripheral blood and bone marrow.

Notably, no DLTs have been observed with the therapy at any of the dose levels examined thus far.

The company also shared plans to continue dose escalation with the therapy in the MRD indication up to 9.0 billion CYNK-001 cells. To strengthen the persistence of the treatment, the expansion arms of MRD and relapsed/refractory AML will include an augmented lymphodepletion protocol comprised of cyclophosphamide at 3600 mg and fludarabine at 120 mg over 4 days vs cyclophosphamide at 900 mg plus fludarabine at 75 mg over 3 days.

In April 2021, the FDA granted an orphan drug designation to CYNK-001 as a potential therapeutic option for patients with malignant gliomas.4 As such, the therapy is also under investigation in patients with glioblastoma multiforme as part of another phase 1 trial (NCT04489420).⁵

To be eligible for enrollment, patients need to have historically confirmed disease at first or second relapse, measurable disease, a Karnofsky performance status of 60 or higher, and acceptable organ function, among other criteria.

Patients who previously received radiation within 12 weeks of their screening MRI; those who were on growth factors with less than 4 weeks of a washout period; those treated with radiotherapy, chemotherapy, or other investigational drugs within 4 weeks; those who received prior cellular or gene therapy; and those with active autoimmune disease, were excluded.

Cohort 1A of the trial will enroll up to 6 patients with recurrent glioblastoma multiforme who will receive intravenous CYNK-001 at a dose of 1.2 x 10⁹ cells on days 0, 7, and 14. From the initial infusion of therapy, patients will be followed for a 42-day DLT period. No other interventions are planned between the last day of treatment.

If DLTs are experienced, cohort 1C, the de-escalation cohort, will include up to 6 patients with recurrent glioblastoma multiforme who will receive the therapy at a dose of 600 x 10⁶ cells on days 0, 7, and 14. These patients will also be followed for DLTs for 42 days post infusion. Cohort 1B, the surgical cohort, will also enroll up to 6 patients, who will be given CYNK-001 at a maximum safe dose of either 1.2 x 10⁹ cells or 600 x 10⁶ cells at days 0, 7, and 14. Patients in this cohort will undergo resection following the last dose of the therapy in the DLT period.

Treatment of cohorts 2A or 2C will only begin after the safety data from cohorts 1A or 1C are determined to be acceptable. Here, patients will first have the Ommaya catheter placement in accordance with institutional policy within 1 week before CYNK-001 infusion on day 0. Cohort 2A will enroll up to 6 patients with recurrent glioblastoma multiforme who will be given the therapy at a dose of 200 x 10⁶ cells +/- 50 x 10⁶ cells intratumorally on day 0, 7, and 14.

Cohort 2C will also include up to 6 patients with recurrent disease who will receive the product at a dose of 200 x 10⁶ cells +/- 50 x 10⁶ cells intratumorally on day 0 and day 7. Lastly, cohort 2B, the surgical intratumoral cohort, will include 6 patients with glioblastoma multiforme who will receive the cellular therapy at a maximum safe dose of either 200 x 10⁶ cells +/- 50 x 10⁶ cells on day 0 and 7.

The primary objectives of the trial are to examine the number of patients who report DLTs with the therapy and toxicities. Important secondary objectives are to evaluate the overall response rate, duration of response, progression-free survival, time to progression, and overall survival.

The safety and efficacy of the cell therapy is also being explored in newly diagnosed patients with multiple myeloma after autologous stem cell transplant, as part of another phase 1 trial (NCT04309084).⁶ The objective of the program is to achieve durable responses with the therapy in these patients with multiple myeloma who are eligible for transplant in the first-line setting.

Another novel agent in the pipeline is CYNK-101, which is manufactured from NK cells extracted from postpartum placentas. The cells are then genetically engineered to boost cell-killing activity when given with a monoclonal antibody.⁷ Preclinical data with the product in combination with an antibody showed that the regimen resulted in cell-killing activity when administered to lymphoma cells in vitro.

Additionally, CYNK-CAR products are being developed as allogeneic, off-the-shelf strategies by modifying genes of the human placental hematopoietic stem cell–derived NK cells. Several CAR constructs that are designed to target hematologic and solid tumor indications are currently under investigation.

References

1. Celularity closes merger with GX Acquisition Corp and provides corporate update. News release. July 16, 2021. Accessed July 16, 2021. https://bit.ly/3hJg0W6
2. Natural killer cell (CYNK-001) infusions in adults with AML (CYNK001AML01). ClinicalTrials.gov. Updated March 2, 2021. Accessed July 16, 2021. https://clinicaltrials.gov/ct2/show/NCT04310592
3. Celularity announces expansion of human placental hematopoietic stem cell derived natural killer cells (CYNK-001) phase 1 trial in patients with acute myeloid leukemia. News release. Celularity. June 29, 2021. Accessed July 16, 2021. https://bit.ly/36Cn151
4. Celularity receives orphan drug designation for natural killer cell therapy CYNK-002 in the treatment of malignant gliomas. News release. Celularity. April 13, 2021. Accessed July 16, 2021. https://bit.ly/3xNRDfF
5. Natural killer cell (CYNK-001) IV infusion or IT administration in adults with recurrent GBM (CYNK001GBM01). ClinicalTrials.gov. Updated July 14, 2021. Accessed July 16, 2021. https://clinicaltrials.gov/ct2/show/NCT04489420
6. Natural killer cell (CYNK-001) infusions in adults with multiple myeloma. ClinicalTrials.gov. Updated April 19, 2021. Accessed July 16, 2021. https://clinicaltrials.gov/ct2/show/NCT04309084
7. NK cell program. Celularity. Accessed July 16, 2021. https://bit.ly/3reREqt