CD33/CLL1 compound CAR T cells in relapsed/refractory AML

During the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress, Fang Liu¹ presented the interim results of a phase I trial (NCT03795779) in which CD33/CLL1 compound chimeric antigen receptor (CAR) T cells were used to treat relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). A total of 30% of patients with AML relapse, and the prognosis for this group of patients is very poor. CAR T-cell therapy is being investigated as a method to target both the leukemic stem cells (LSCs) and the abnormal blasts in patients with AML.

CD33 and CLL are expressed on AML blast cells and on normal myeloid cells. CLL1 is also present on certain LSCs that have been associated with disease progression and is rarely expressed by normal hematopoietic stem cells, whereas CD33 is commonly expressed on the latter.² By targeting both of these markers, the team hope to remove both the bulky AML blast component and the LSCs along with myeloablation.

Patients and methods

The primary endpoint of this phase I clinical trial was safety. The secondary endpoints of efficacy and engraftment after reduced-intensity conditioning hematopoietic stem cell transplant (HSCT) were also analyzed. The study is still ongoing, with an estimated completion date in September 2020.

Patient characteristics are shown in Table 1. A total of nine patients are included in this study so far, with the majority of patients having undergone at least three rounds of chemotherapy. Out of all patients, seven had de novo AML, one had chronic myelogenous leukemia in accelerated phase, and one had juvenile myelomonocytic leukemia.

Table 1. Patient characteristics¹

 Treatment schema

• Apheresis was performed to collect stem cells
• Patients were treated with low-dose chemotherapy for 2–3 weeks during CAR T-cell manufacture to reduce tumor burden
• Bone marrow evaluations were carried out
• Conditioning with fludarabine/cyclophosphamide
• CAR T-cell infusion (three dose levels [DL]: DL1, 1 × 10⁶/kg; DL2, 2 × 10⁶/kg; DL3, 3 × 10⁶/kg)
• Safety assessments
• Bone marrow evaluation (Day 14–28)
• Within 40 days, HSCT was performed
• Follow-up

Key points

Safety profile

A summary of the incidence of cytokine release syndrome (CRS) and CAR T-cell-related encephalopathy (CRES) is shown in Table 2. All but Patient 7 experienced CRS, most frequently in the second week of treatment and lasting up to 2 weeks. CRES occurred in four patients, with the majority being of Grade 3. Onset of CRES was in the first few weeks of treatment. All CRS and CRES were resolved after treatment.

Table 2. Incidence of CRS and CRES and treatment¹

Grade 4 pancytopenia was experienced in all patients, with the next most frequent adverse event being a mild elevation of liver enzymes. Grade 4 sepsis was experienced by three patients. There were also three cases of pneumonia Grade 3, two fungal infections of Grade 3, and four cases of mild diarrhea.

CAR T-cell persistence

Levels of CAR T cells in the peripheral blood were measured by flow cytometry. Levels tended to peak between Week 1−3 and reached undetectable levels by the time of HSCT (Day 30+).

Outcomes

Of the patients involved in the study, seven achieved measurable residual disease (MRD) negativity, while two exhibited no response. Of the patients who were MRD negative, six underwent HSCT (five with reduced-intensity conditioning and one with myeloablative conditioning), resulting in five successfully engrafted patients with persistent full chimerism. One patient died of sepsis prior to engraftment.

Conclusion

CD33-CLL1 compound CAR T cells showed effective antitumor activity for R/R AML in this study, and although signs of toxicity were seen, they were manageable. Compound CAR T cells could serve as a dual targeting therapy for concomitant bulky tumor and LSC elimination but may also serve as an effective conditioning regimen prior to HSCT for treating patients with R/R AML.