12月3日，第58届美国血液学年会（ASH，12月3日~6日）于美国圣地亚哥召开。其间，在“
该研究首次评估了靶向CD22的嵌合抗原受体（CAR）在人体中的应用。Terry J. Fry教授说，这是首个成功挽救CD19阴性ALL的CAR疗法。在这之前，研究人员已经成功将靶向CD19的CAR-T细胞疗法用于复发/难治性ALL。对表达缺失的相当一部分ALL患者CD19，CD22是一种很好的替代靶向。
该1期研究招募了CD22阳性的儿童和成人血液恶性肿瘤患者。所有患者接受了外周血单核细胞的自体白细胞去除术。采用anti-CD3/CD28/beads对分离后的CD22+T细胞进行体外扩增，随后用含抗CD22 CAR的慢病毒载体上清液，培养7~10天。先给予患者淋巴细胞去除性化疗，随后给予细胞输注。
Fry教授呈现了该研究中前16名患者的研究结果。所有患者之前至少接受过1次异基因干细胞移植，11名患者之前接受过CD19靶向治疗，9名患者CD19表达阴性或CD19表达减少。
研究人员检测了三种剂量：3 x 105、1 x 106和3 x 106。大多数CD19试验中应用最多的剂量是 1 x 106，作为生物活性剂量。
结果发现，对于接受1 x 106或更高剂量输注的患者，完全缓解率为80%，并且在输注1个月后未检测出残留病变。另外1个接受低剂量输注的患者也达到了缓解。随后，研究人员注意到，1名患者的缓解期超过1年，1名持续6个月，1名持续了3个月。但9名达到缓解的患者中，6名患者复发。所有发生响应的患者的外周血、CSF和骨髓中均可发现抗CD22 CAR-T细胞。28天时（+/- 4天），研究人员评估了患者响应情况，在9名可评估响应的患者中，4名患者达到了完全骨髓缓解，并且最小残留病变均为阴性。
该研究表明，首个人抗CD22-CAR T细胞疗法治疗先前接受过CAR治疗后的白血病，安全可行，具有临床活性。CAR阴性或先前接受抗CD19 CAR疗法治疗或CD19阴性的患者，均可达到最小残留病变阴性。
摘要详情
650 Minimal Residual Disease Negative Complete Remissions Following Anti-CD22 Chimeric Antigen Receptor (CAR) in Children and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)
Background: Despite the success of anti-CD19 chimeric antigen receptor (CAR) therapy for relapsed/refractory ALL, not all respond and CD19-negative escape has been observed. To overcome this problem and to test an alternative target, we developed an anti-CD22 CAR. Widely expressed on B-lineage leukemia and lymphomas, CD22 represents an ideal target. The primary objectives of this phase I dose escalation study were to determine the feasibility of producing anti-CD22 CAR cells and to assess the safety of administering escalating doses of anti-CD22-CAR T cells in children and young adults with relapsed or refractory CD22+ B cell malignancies. Secondary objectives include determination of anti-leukemia effects, measurement of persistence of anti-CD22 CAR T cells, and evaluation of cytokine profiles. We report interim results based on the first 9 enrolled subjects in this first-in-human testing of anti-CD22 CAR therapy.
Design: Children and young adults with relapsed/refractory CD22+ hematologic malignancies were eligible. Study endpoints included toxicity, feasibility, and clinical responses. All enrolled subjects underwent autologous leukopheresis for peripheral blood mononuclear cells. Cells were then CD3+ enriched and cultured in the presence of anti-CD3/-CD28 beads followed by lentiviral vector supernatant containing the anti-CD22 (M971BBz) CAR, with culture duration of 7-10 days. Subjects began lymphodepleting chemotherapy with fludarabine 25 mg/m2 on Days –4, –3 and –2 and cyclophosphamide 900 mg/m2 on day –2 followed by cell infusion on Day 0. Dose level 1(DL-1) started at 3 x 105 transduced T-cells/recipient weight (kg), with DL- 2 at 1 x 106transduced T cells/kg, respectively.
Results: We report on outcomes for the first 9 subjects enrolled and treated. The median age was 20 years (range, 7-22 years), and all had CD22+ ALL. All 9 subjects had previously undergone at least one prior allogeneic hematopoietic stem cell transplant, and 2 patients had received 2 prior transplants. Seven subjects had previously received treatment with anti-CD19 CAR-T cell therapy of whom 6 had a CD19 negative/dim antigen escape. All subjects had CD22 expression on > 99% of their malignancy, with a median site density of 2589 molecules per cell (range 846-13452). Dose-escalation was as follows: 6 subjects treated at DL-1 due to expansion at this level following DLT in the second subject with grade 3 diarrhea; 3 subjects treated at DL-2 without DLT. CAR expansion and cytokine release syndrome (CRS) was seen in 6 patients with a maximum CRS grade 2. Anti-CD22 CAR cells were detected in the peripheral blood, CSF and bone marrow of all responders. Clinical responses were evaluated at day 28 (+/- 4 days). Four of 9 (44%) subjects evaluable for response attained a complete marrow remission, all of whom were MRD negative. This included all 3 subjects treated at the second dose level with a sustained remission at 3 months.
Conclusions: This first-in-human anti-CD22 CAR T-cell therapy is safe, feasible and clinically active in patients with leukemia who have undergone prior CAR therapy. MRD negative complete remissions were seen in patients who were both CAR-naïve or had previously been treated with anti-CD19 CAR and were CD19 negative. Accrual is ongoing.
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