CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria

* Participants must have signed and dated a current IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. Patients must have the ability to understand a written informed consent document, and the willingness to sign it.
* Consent must be obtained before the performance of any protocol related procedures that are not part of normal patient care.
* Patients must have histologically confirmed advanced solid tumor that is metastatic or unresectable and who have progression of disease on standard therapy. Historical pathology reports will suffice to meet this criterion, repeat biopsy confirmation is not needed.
* Age \>18 years
* At least one tumor nodule greater than or equal to 1 cm in long axis diameter amenable to surgical harvest as an out-patient procedure for DP CD8 TIL production.
* Patients must meet the laboratory criteria below within 28 days prior to the first dose of study treatment:

  * Adequate Bone Marrow Function: WBC \>3,000/mcL; Absolute neutrophil count \>1,500/mcL; Hemoglobin \> 8 gm/dL; Platelets \>100,000/mcL
  * Adequate hepatic function: total bilirubin; ≤ 2.0 mg/dL except in patients with Gilbert's Syndrome who must have a total bilirubin ≤ 3.0 mg/dL; AST(SGOT) \< 2.5 X institutional upper limit of normal; ALT(SGPT) \< 2.5 X institutional upper limit of normal
  * Adequate renal function: Serum creatinine \< 1.5 x ULN, unless creatinine clearance ≥ 40 mL/min (measured or calculated using the Cockcroft-Gault formula)
* Women of childbearing potential must not be pregnant and must avoid becoming pregnant while on treatment and for 6 months following treatment discontinuation. Men must agree to avoid fathering a child while on treatment and for 6 months following the last dose of treatment.
* ECOG Performance Status 0-1 or equivalent Karnofsky score at the time of enrollment.
* Patients need to have received at least 1 prior line of systemic therapy before participation in this protocol and have no therapeutic options with possibility of cure or durable remission.
* Subjects with squamous cell carcinoma of the head and neck must have received a platinum containing chemotherapy regimen for treatment of primary tumor in locally advanced, or metastatic settings and must have received an anti-PD-1/ PD-L1 as monotherapy or in combination with chemotherapy.
* Subjects with melanoma must have received an anti-PD-1/ PD-L1 inhibitor as monotherapy or in combination with anti-CTLA-4 inhibitor or anti-PD-1 in combination with anti-LAG-3 determined to have either primary or secondary CPI resistance.
* Subjects with tumors having known actionable molecular alterations such as BRAF and MEK for which FDA-approved medications are available must have progressed on directed molecular therapy.

Exclusion Criteria:

* Active brain metastases or leptomeningeal metastases. Participants with brain metastases are eligible if these have been treated and there is no MRI evidence of progression for at least 4 weeks after treatment is complete. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents). Stable doses of anticonvulsants are allowed. Treatment for CNS metastases may include stereotactic radiosurgery (e.g. Gamma Knife, Cyber Knife, or equivalent) or neurosurgical resection. Patients who received whole brain radiation therapy are not eligible.
* Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results (e.g., a condition associated with diarrhea or acute diverticulitis).
* Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or localized carcinoma of the prostate, cervix, or breast.
* Participants with an active, known or suspected autoimmune disease requiring active treatment. Participants with type I diabetes mellitus, hypothyroidism requiring only hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
* Requirement for greater than physiological doses of corticosteroids (\> 10 mg daily prednisone equivalent)
* Requirement for other immunosuppressive medications including but not limited to anti-TNF antibodies, mycophenylate mofetil and methotrexate. Inhaled, intra-nasal or topical steroids are permitted in the absence of active autoimmune disease.
* History of organ or tissue transplant that requires systemic use of immune suppressive agents.
* Active infection requiring systemic therapy within 14 days prior to enrollment.
* Patients who have had chemotherapy, radiotherapy, biologics, other anti-neoplastic or investigational agents, and/or other antitumor treatment including immunotherapy within 2 weeks (14 days) of Day -5, or those who have not recovered from adverse events related to therapies administered more than 4 weeks (28 days) earlier, are not eligible to enroll. All adverse events related to prior therapy must have improved to grade 1 or better before study participation.
* Focal radiotherapy (examples include SRS, Palliative or MRI-Linac) completed at least 2 weeks (14 days) prior to the first dose study treatment are permitted to enroll.
* Patients with evidence of ischemia on exercise tolerance test, stress thallium study, or baseline EKG are excluded.
* DLCO, FEV1 or FEV1/FVC less than 65% of predicted due to clinically significant underlying pulmonary disease. For any pulmonary function test values less than predicted values, the PI will review, and document the patient's suitability for high-dose IL-2 therapy.
* Allergy to any of the antibiotics used in the cell production.
* Tumor harvest with no detectable DP CD8 TIL.

主要终点：Safety of DP CD8 TIL · Frequency and severity of treatment-related adverse events as assessed by CTCAE v5.0 in participants treated with DP CD8 TIL adoptive cell therapy with and without ex vivo siRNA PD-1 modulation after lymphodepleting chemotherapy and followed by high-dose and low-dose IL-2. · 12 weeks after cell infusion, then per PI discretion
次要终点：Efficacy of DP CD8 TIL；Compare persistence of DP CD8 TIL and DP CD8 TIL KD in peripheral blood

• DP CD8 TIL · EXPERIMENTAL · Adoptive Cell Transfer of tumor infiltrating lymphocytes that were selected for tumor reactivity by the expression of cell surface proteins CD39 an CD103 and expanded in vitro. A suspension of 1-40 billion cells will be delivered one time by intravenous infusion.
• DP CD8 TIL KD · EXPERIMENTAL · Adoptive Cell Transfer of tumor infiltrating lymphocytes that were selected for tumor reactivity by the expression of cell surface proteins CD39 and CD103 and expanded in vitro in the presence of PH-762, a silencing RNA that reduces the expression of the checkpoint inhibitor PD-1. A suspension of 1-40 billion cells will be delivered one time by intravenous infusion.

The subject of this study is the adoptive transfer of selected autologous tumor infiltrating lymphocytes (TIL) after in vitro expansion for the treatment of solid tumor malignancies. The TIL selection process is based on evidence showing that CD8+ TIL which co-express both CD39 and CD103 harbor the bulk of tumor-reactivity and that the remaining CD8 TIL is mainly composed of non-tumor reactive bystander cells. All of the expanded TIL that are produced (1-40 billion are expected) will be delivered in the form of a cell suspension to the participants by intravenous infusion. It is proposed that these selected TIL will produce a more potent and efficacious treatment of late-stage cancer.