美国首例CRISPR临床试验细节

美国使用CRISPR治疗疾病的第一个人体试验即将开始。由宾夕法尼亚大学领导的这项试验将使用CRISPR基因编辑工具修改免疫细胞，攻击三种不同类型的癌症。欢迎欣赏我们同期发布的文章《重磅 | 美国首次CRISPR人体试验即将开始》！

下面是这个临床试验的一些细节。信息转自clinicaltrials.gov网站，汇总于此，供感兴趣的朋友们参考。

NY-ESO-1-redirected CRISPR (TCRendo and PD1) Edited T Cells (NYCE T Cells)

Sponsor:

University of Pennsylvania

Information provided by (Responsible Party):

University of Pennsylvania

Brief Summary:

This is a first-in-human trial proposed to test HLA-A*0201 restricted NY-ESO-1 redirected T cells with edited endogenous T cell receptor and PD-1.

Condition of disease:

Multiple MyelomaMelanomaSynovial SarcomaMyxoid/Round Cell Liposarcoma

Intervention/treatment

Biological: NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1Drug: CyclophosphamideDrug: FludarabineDevice: NY-ESO-1 expression testing

Study Design:

Study Type  :	Interventional  (Clinical Trial)
Estimated Enrollment  :	18 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Other
Official Title:	Phase 1 Trial of Autologous T Cells Engineered to Express NY-ESO-1 TCR and CRISPR Gene Edited to Eliminate Endogenous TCR and PD-1 (NYCE T Cells)
Anticipated Study Start Date  :	January 2018
Estimated Primary Completion Date  :	January 2033
Estimated Study Completion Date  :	January 2033

Arms and Interventions:

Arm: Experimental: Multiple Myeloma

Intervention/treatment:

Biological: NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1

Autologous T cells transduced with a lentiviral vector to express NY-ESO-1 and electroporated with CRISPR guide RNA to disrupt expression of endogenous TCRα, TCRβ and PD-1.

Other Name: NYCE T cells

Drug: Cyclophosphamide

a cytotoxic chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Device: NY-ESO-1 expression testing

Testing to determine if NY-ESO-1 is expressed on tumor tissue.

Arm: Experimental: Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)

Intervention/treatment:

Biological: NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1

Autologous T cells transduced with a lentiviral vector to express NY-ESO-1 and electroporated with CRISPR guide RNA to disrupt expression of endogenous TCRα, TCRβ and PD-1.

Other Name: NYCE T cells

Drug: Cyclophosphamide

a cytotoxic chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Drug: Fludarabine

a chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Device: NY-ESO-1 expression testing

Testing to determine if NY-ESO-1 is expressed on tumor tissue.

Arm: Experimental: Melanoma

Intervention/treatment:

Biological: NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1

Autologous T cells transduced with a lentiviral vector to express NY-ESO-1 and electroporated with CRISPR guide RNA to disrupt expression of endogenous TCRα, TCRβ and PD-1.

Other Name: NYCE T cells

Drug: Cyclophosphamide

a cytotoxic chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Drug: Fludarabine

a chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Device: NY-ESO-1 expression testing

Testing to determine if NY-ESO-1 is expressed on tumor tissue.

Outcome Measures

Primary Outcome Measures:

1. Determine safety profile of a single infusion of NYCE T cells by monitoring the frequency and severity of adverse events assessed by the National Cancer Institute (NCI) - Common Toxicity Criteria (v4.03) [ Time Frame: 5 years ]
   

2. Evaluate Manufacturing Feasibility of NYCE T Cells. [ Time Frame: 5 years ]

   Evaluate the percentage of manufacturing products that do not meet release criteria for vector transduction efficiency, gene disruption T cell product purity, viability, sterility or due to tumor contamination.

Secondary Outcome Measures:

1. Percentage of patients achieving CR before or at Month 6 [ Time Frame: 5 years ]
   

2. Overall survival (OS) [ Time Frame: 5 years ]
   

3. Duration of remission (DOR) [ Time Frame: 5 years ]
   

4. Progression- free survival (PFS) [ Time Frame: 5 years ]
   

5. Cause of death (COD) when appropriate [ Time Frame: 5 years ]

Eligibility Criteria:

Ages Eligible for Study:	18 Years and older   (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Inclusion Criteria:

1. Subjects with a confirmed diagnosis of relapsed refractory multiple myeloma, melanoma, synovial sarcoma, or myxoid/round cell liposarcoma (MRCL) as follows:

a. Multiple Myeloma i. Subjects must have a confirmed prior diagnosis of active MM as defined by the IMWG criteria121.

ii. Subjects must have relapsed or refractory disease after either one of the following:

1. At least 3 prior regimens, which must have contained an alkylating agent, proteasome inhibitor, and immunomodulatory agent (IMiD) OR

2. At least 2 prior regimens if "double-refractory" to a proteasome inhibitor and IMiD, defined as progression on or within 60 days of treatment with these agents.

3. Note: Induction therapy, stem cell transplant, and maintenance therapy, if given sequentially without intervening progression, should be considered as 1 "regimen".

iii. Subjects must be at least 90 days since autologous stem cell transplant, if performed.

iv. Toxicities from prior therapies, with the exception of alopecia or peripheral neuropathy attributable to bortezomib, must have recovered to grade ≤ 2 according to the CTC 4.0 criteria or to the subject's prior baseline.

v. Subjects must have measurable disease per IMWG criteria on study entry, which must include at least 1 of the following:

1. Serum M-spike ≥ 0.5 g/dL*

2. 24 hr urine M-spike ≥ 200mg

3. Involved serum free light chain (FLC) ≥ 50 mg/L with abnormal ratio

4. Measurable plasmacytoma on exam or imaging

5. Bone marrow plasma cells ≥ 20%

• Note: Patients with IgA myeloma in whom serum protein electrophoresis is deemed unreliable, due to co-migration of normal serum proteins with the paraprotein in the beta region, may be considered eligible as long as total serum IgA level is elevated above normal range.

  b. Melanoma i. Subjects must have a confirmed prior diagnosis of melanoma. ii. Progressed after at least 2 therapy lines. iii. Patients must have measurable disease per RECIST 1.1 in order to allow assessment of an anti-tumor response.

  c. Synovial Sarcoma or Myxoid/Round Cell Liposarcoma (MRCL) i. Subjects must have a confirmed prior diagnosis of synovial sarcoma or MRCL. ii. Patients with proven metastatic disease or surgically inoperable local recurrence that have failed first line treatment.

iii. Patients must have measurable disease per RECIST 1.1 in order to allow assessment of an anti-tumor response.

• 2. Provides written, informed consent.

• 3. Subjects ≥ 18 years of age.

• 4. ECOG performance status of 0-2.

• 5. Documented NY-ESO-1 expression on tumor tissue.

• 6. HLA-A*201 positive

• 7. Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.

• 8. Adequate vital organ function as defined by:

1. Serum creatinine ≤ 2.5 or estimated creatinine clearance ≥30 ml/min and not dialysis-dependent.

2. Absolute neutrophil count ≥1000/μl and platelet count ≥50,000/μl (≥30,000/μl if bone marrow plasma cells are ≥50% of cellularity for MM patients).

3. SGOT ≤ 3x the upper limit of normal and total bilirubin ≤ 2.0 mg/dl (except for patients in whom hyperbilirubinemia is attributed to Gilbert's syndrome).

4. Left ventricular ejection fraction (LVEF) ≥ 45%. LVEF assessment must have been performed within 8 weeks of enrollment.

Exclusion Criteria:

• 1. Pregnant or nursing (lactating) women.

• 2. Have inadequate venous access for or contraindications to leukapheresis.

• 3. Have any active and uncontrolled infection.

• 4. Active hepatitis B or hepatitis C

• 5. HIV infection.

• 6. Any uncontrolled medical or psychiatric disorder that would preclude participation as outlined.

• 7. NYHA Class III or IV heart failure (see Section 16), unstable angina, or a history of recent (within 6 months) myocardial infarction or sustained (>30 seconds) ventricular tachyarrhythmias.

• 8. Received prior gene therapy or gene-modified cellular immunotherapy. Subject may have received, however, non-gene-modified autologous T-cells in association with an anti-myeloma vaccine (e.g., hTERT or MAGEA3) or vaccination against infectious agents (e.g., influenza or pneumococcus) as was performed on our previous studies.

• 9. Active auto-immune disease, including connective tissue disease, uveitis, sarcoidosis, inflammatory bowel disease, or multiple sclerosis, or have a history of severe (as judged by the principal investigator) autoimmune disease requiring prolonged immunosuppressive therapy.

• 10. Prior allogeneic stem cell transplant.

• 11. Prior or active central nervous system (CNS) involvement (e.g. leptomeningeal disease, parenchymal masses) with myeloma. Screening for this (e.g. with lumbar puncture) is not required unless suspicious symptoms or radiographic findings are present. Subjects with calvarial disease that extends intracranially and involves the dura will be excluded, even if CSF is negative for myeloma.

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