CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Subjects with histologically or cytologically confirmed history of IDH-wild type glioblastoma

  * Phase 1b and Arm B of Phase 2: Subjects must have completed no more than one standard therapy for glioblastoma, have received no prior Avastin® therapy (unless solely used for edema management) and be eligible for resection
  * Arms A and C: Subjects must have newly diagnosed, treatment naïve glioblastoma
  * Phase 1b and Arm B and Arm C: Subjects must have a partially matched haploidentical or matched related donor.
* Subjects with magnetic resonance imaging (MRI) features consistent with and suspicious for recurrent malignant glioma in Phase 1b and Arm B.
* Agreeable to inserting and maintaining a Rickham catheter.
* ≥ 18 years of age.
* Karnofsky Performance Status ≥ 70%
* Female subjects of childbearing potential must have a negative urine/serum pregnancy test within 72 hours of study enrollment. Female subjects of childbearing potential are those who have not been surgically sterilized or have not been free of menses for \> 2 years.
* Male subjects and their female partners and female subjects of childbearing potential must be willing to use a combination of two methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study.

Exclusion Criteria:

* Subject in Arm A or donor from Phase 1b, Arms B, and Arm C received vaccinations within 4 weeks or underwent surgery (major or minor) within 72 hours before leukapheresis collection.
* Cellular immunotherapy or gene therapy or within six weeks prior to entering the study, surgical resection or alkylating agent chemotherapy within four weeks prior to entering the study, receiving tumor treating fields (TTF) Optune therapy, or have received experimental immunotherapy at any time
* Subjects receiving any other investigational agents concurrently while on study.
* Have not recovered from adverse events (≤ Grade 1) from previously administered therapy. Subjects with alopecia unless of immune origin are an exception to this criterion and may qualify for this study
* Have received prior treatment with an allogeneic therapy, including bone marrow or solid tumor transplant.
* Concurrent malignancy or an active second malignancy. Subjects with a history of second malignancy must have no evidence of cancer for two years prior to enrolment or have a surgically cured cancer with low risk of recurrence to enroll. Discuss with medical monitor prior to enrolment.
* Contraindication to the placement of an intracranial access device (Rickham catheter) at the time of surgery.
* Prior history of encephalitis, multiple sclerosis, or other CNS infection \<1 year prior to glioblastoma diagnosis.
* Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, or any other medical condition that precludes surgery. Also, medical/surgical/psychiatric illness/social situations that would limit compliance with study requirements or confound interpretation of safety and efficacy data. Subjects with a history of seizure as a result of their glioblastoma must be seizure free and on appropriate anti-epileptic medication for 3 weeks prior to dosing with the investigational agent.
* Allergies/hypersensitivity to amino bisphosphonates such as Zoledronate®, Pamidronate® or similar.
* History of HIV or active hepatitis even if well controlled or history of an autoimmune condition.

主要终点：Autologous Phase 2, Arm A in newly diagnosed glioblastoma: 12-month overall survival (OS) rate · Date of first dose to date of death by any cause · 12 Months；Allogeneic Phase 1b, establishes the recommended phase 2 dose (RP2D) for phase 2 allogeneic arms and subject or product characteristics that will optimize manufacturing · \<30% dose limiting toxicity (DLT) observed with dose · 28 days；Allogeneic Phase 2, Arm B confirmed recurrent glioblastoma, 9-month overall survival (OS) · Date of first dose to date of death by any cause · 9 Months；Allogeneic Phase 2, Arm C newly diagnosed glioblastoma, 12-month overall survival (OS) rate · Date of first dose to date of death by any cause · 12 Months
次要终点：Assessment of safety；Assessment of tolerability；Overall response rate (ORR)；Time to progression (TTP)；Progression free survival (PFS)；Definition of product characteristics

• 1) Autologous Newly Diagnosed Disease: Phase 2 Arm A · EXPERIMENTAL · Arm A subjects with newly diagnosed disease will receive autologously derived, genetically modified gamma-delta T cells administered with maintenance temozolomide.
• 2) Allogeneic Relapsed Disease: Phase 1b and Phase 2 · EXPERIMENTAL · Phase 1b subjects with relapsed disease will have allogeneic derived, genetically modified gamma-delta T cells administered with temozolomide
• 3) Allogeneic Newly Diagnosed Disease: Phase 2 Arm C · EXPERIMENTAL · Arm C subjects with newly diagnosed disease will receive allogeneic derived, genetically modified gamma-delta T cells administered with maintenance temozolomide.

This multicenter, Phase 1b/2 study is being conducted to determine if the experimental cell therapy is safe, tolerable and can delay the return of cancer in patients with a newly diagnosed or recurrent glioblastoma multiforme (GBM) in combination with standard chemotherapy treatment temozolomide (TMZ). If there is a 25% or greater improvement in survival in this study then the therapy should be studied further.