Pilot Study of Autologous T Lymphocytes With Antibody-Dependent Cell Cytotoxicity in Patients With CD20-Positive B-Cell Malignancies
试验速览
- 阶段
- 1 期
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Performance status assessed by age-dependent Performance Scores
研究概览
简要总结
Despite advancement in chemotherapy, radiotherapy and haematopoietic stem cell transplant (HSCT), and the recent introduction of more targeted therapies, a substantial proportion of patients with B-cell malignancies, such as B-cell chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin's lymphoma (NHL) still succumb to their malignancies. For CLL and low-grade NHL, cure is achievable only with HSCT but such aggressive approach is not justified as the initial therapy for most patients who have indolent disease; when disease has progressed, transplant is either not feasible or ineffective. For high-grade B-cell NHL, the availability of Rituximab has improved disease outcome but treatment failure portends nearly inevitable death from disease or treatment-related complications. Thus, newer, more effective therapies for patients with B-cell malignancies are urgently needed.
The present study translates recent laboratory findings into clinical application. In patients with B-cell malignancies receiving the anti-CD20 antibody Rituximab as standard therapy, the study aims to assess the feasibility and safety, as well as explore the efficacy, of infusing autologous T-lymphocytes engineered to express a CD16-41BB-CD3zeta chimeric receptor which mediates antibody-dependent cell cytotoxicity. Receptor expression is achieved by electroporation of mRNA.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 80 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: 6 months to 80 years old.
- •i) Diagnosis of aggressive CD20+ B-NHL with measurable tumor burden (by imaging, flow cytometry and/or PCR) post-treatment. This includes patients with persistent disease following more than 2 lines of chemotherapy, as well as patients who relapse following autologous transplantation, and in whom further salvage therapy has produced only a partial remission or where no effective salvage therapy available. Patients with bulky disease who require immediate salvage therapy will not be eligible.
- •OR ii) Diagnosis of poor risk indolent CD20+ B-NHL or Chronic Lymphocytic Leukemia. This includes high risk CLL cases with early relapse (<12 months following purine analog containing treatment or <24 months following autologous transplant), or with 17p deletion needing treatment, and who are not candidates (or refuses) allogeneic transplantation. Patients with advanced progressive indolent B-NHL with relapsed, refractory disease who have failed more than 2 lines of treatment (including autologous transplantation) may also be considered.
- •Shortening fraction greater than or equal to 25%.
- •Glomerular filtration rate greater than or equal to 50 ml/min/1.73 m
- •Pulse oximetry greater than or equal to 92% on room air.
- •Direct bilirubin less than or equal to 3.0 mg/dL (50 mmol/L).
- •Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal unless determined to be directly due to disease.
- •Aspartate transaminases (AST) is no more than 2 times the upper limit of normal unless determined to be directly due to disease.
- •Karnofsky or Lansky performance score of greater than or equal to
- •No clinical history of or overt autoimmune disease.
- •No past history of previous severe adverse reactions to rituximab, eg. cytokine release syndrome
- •Has recovered from all acute NCI Common Toxicity Criteria grade II-IV non-hematologic acute toxicities resulting from prior therapy per the judgment of the PI.
- •Is not receiving more than the equivalent of prednisone 10 mg daily.
- •Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).
- •Not lactating.
排除标准
- •Failure to meet any of the inclusion criteria
研究组 & 干预措施
T-cell therapy + Rituximab + IL-2
Patients will undergo apheresis procedure and T cell expansion will be done in the laboratory. All patients will receive Rituximab on day -2 and IL-2 three times per week for one week starting on day -1 (dose 1 of 3). IL-2 dosing will be continued 3 times per week for one week (3 doses total).
On Day 0, T cell modification in the laboratory and T cell infusion in the patient will be done.
A disease status evaluation will be conducted approximately 4 weeks post-T cell infusion.
干预措施: T-cell therapy + Rituximab + IL-2 (Drug)
结局指标
主要结局
Performance status assessed by age-dependent Performance Scores
时间窗: One-month (30 days) after the last T cell infusion
Using KARNOFSKY PERFORMANCE STATUS SCALE (Recipient Age ≥ 16 years) and LANSKY PERFORMANCE STATUS SCALE (Recipient Age \< 16 years)
Toxicity criteria
时间窗: One-month (30 days) after the last T cell infusion
Participants will be monitored for toxicity for a period of one-month (30 days) after the last T cell infusion. Monitored toxicities will include the following: 1. grades III-IV allergic reactions related to infusion; 2. grade IV neutropenia lasting greater than 28 days; 3. grade IV infection uncontrolled for greater than 7 days; 4. grade IV other adverse events; 5. treatment-related death (grade V).
Disease response criteria
时间窗: One-month (30 days) after the last T cell infusion and at intervals thereafter till progression (approximately every 3 months for about a year)
Response criteria follow those defined by NCCN Guidelines version 4.2011 for CLL and NHL. For monitoring of treatment response, patients with CLL and NHL will have PET-CT scan at approximately 1 month before and after infusion and at intervals thereafter till progression. Peripheral blood and bone marrow studies (the latter only if bone marrow is involved pre-treatment) will be done to determine levels of residual disease by using established flow cytometric and molecular MRD assays.
Persistence of CD16+ T cells and impact on B cell function
时间窗: Up to approximately month
1. The in vivo expression of anti-CD16V-BB-zeta on T cells will be monitored by flow cytometry. For this purpose, 10 ml of blood will be taken on Days 0, 1 and every other day after each infusion until infused T cells expressing the receptor become undetectable. 2. Longer term impact on the suppression of B cell function will also be monitored by assaying B cell numbers and immunoglobulin levels.
次要结局
未报告次要终点