Fast TILs to Treat Metastatic Cancer Patients With Pleural Disease

This is a first-in-human Phase 1 trial of short-term expanded pleural T cells to treat cancer metastatic to the pleura. Expanded cells will be delivered intrapleurally in combination with intrapleural IL-2, administered at a dose that ensures high local concentration while minimizing systemic exposure.

Ancillary studies conducted in conjunction with the trial will leverage drained pleural effusions collected before and after intervention to determine why the intervention is succeeding or failing.

• locally manufactured adoptive cellular therapy (ACT) product (Biological), also known as ACT, Fast TIL: Single dose, intrapleural delivery (via indwelling pleural catheter) of adoptive cellular therapy (ACT) product derived from autologous pleural infiltrating T-cells.
• Interleukin-2 (Drug), also known as IL-2, Proleukin: Low dose Interleukin-2 (IL-2) will also be administered intrapleural at the dose of 20 milliliters (mL) at 1 x 10⁵ International Units (IU)/mL starting approximately 2 hours after ACT infusion and every 8 to 16 hours thereafter, as tolerated, for up to 4 doses (total 8 x 10⁶ IU).

Primary outcomes

• Document the feasibility of local manufacture of ACT product from drained pleural effusions using the CliniMACS Prodigy® device [30 days]: flow cytometry for cellular ACT identity
• Document the feasibility of local manufacture of ACT product from drained pleural effusions using the CliniMACS Prodigy® device [30 days]: cytotoxicity assays for ACT potency
• Document the feasibility of local manufacture of ACT product from drained pleural effusions using the CliniMACS Prodigy® device [30 days]: flow cytometry for cellular ACT purity
• To demonstrate the safety of intrapleural administration of the locally manufactured ACT product plus Interleukin 2 (IL-2) to study patients [5 years]: incidence of Treatment-Emergent Adverse Events (Safety) of intrapleural administration of the locally manufactured ACT product, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary outcomes

• To document changes in the pleural fluid secretome secondary to local therapeutic ACT product infusion. [30 days]: changes in the pleural fluid secretome secondary to local therapeutic ACT product infusion using Luminex assays
• To document changes in the pleural cellular composition secondary to local therapeutic ACT product infusion [30 days]: changes in the pleural cellular composition secondary to local therapeutic ACT product infusion via flow cytometry
• To document the overall response rates to therapy [60 days]: as measured by PET CT scan, using mRECIST criteria
• To document the complete response rates to therapy [60 days]: as measured by PET CT scan, using mRECIST criteria

Sex: All, ages: 18 Years to 79 Years

Inclusion Criteria:

1. Patients with symptomatic, biopsy-proven malignant to the pleura, or mesothelioma with pleural effusions. Patients must have received and be refractory to available standard of care (SOC) therapy specific to their cancer type and must have exhausted or failed available standard of care with clinical benefit.
2. Patients will be ≥ 18 and < 80 years of age.
3. Female patients of childbearing potential must have a negative urine or serum pregnancy test and if sexually active must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), an injectable contraceptive (such as Depo-Provera), or an oral contraceptive. Active contraception should continue for at least 12 months after ACT administration. Male participants must be willing to practice birth control from the time of enrollment on this study and for 4 months after receiving the preparative regimen.
4. Cardiac ejection fraction ≥ 0.45 by Multiple-Gated Acquisition (MUGA) or echocardiography.
5. No requirement for supplemental oxygen and no dyspnea immediately after effusion drainage.
6. ECOG Performance Status 0 or 1.
7. Patients must have an expected survival > 12 weeks.
8. Patients must be able to comprehend the risks and methods used in this clinical trial and independently consent to participate.
9. Patients must consent to collection of demographic and clinical data.

Exclusion Criteria:

1. Patients with breast, kidney, lung, pancreatic, prostate, ovarian, rare cancers, and melanoma.
2. Infection with Human Immunodeficiency Virus (HIV) and active viral replication. Patients with an undetectable viral load on Anti-retroviral Therapy (ART) can be considered for participation on this protocol.
3. Infection with hepatitis B and active viral replication.
4. Infection with hepatitis C and active viral replication.
5. Patients currently being treated for bacterial, fungal or viral infection.
6. Documented myocardial infarction within 6 months of study participation and/or symptomatic coronary artery or valvular disease or uncontrolled arrhythmia.
7. Investigational drug use within 30 days before effusion collection.
8. Cytotoxic anti-cancer or radiation therapy administration within 2 weeks of effusion collection. The exclusion does not apply to patients receiving monoclonal antibody therapy targeting immune checkpoint molecules.
9. Corticosteroid therapy > 10 milligrams (mg) of prednisone (biological equivalent) daily within 2 weeks before effusion collection.
10. Immunosuppressive therapy that cannot be stopped for 4 weeks prior to effusion collection as deemed by the prescribing physician.
11. Laboratory abnormalities that indicate clinically significant hematological, hepatobiliary, or renal disease:

    AST/SGOT > 2.0 times the upper limit of normal ALT/SGPT > 2.0 times the upper limit of normal Total bilirubin > 2.0 times the upper limit of normal, unless patient has Gilbert Syndrome (>3.0 times the upper limit of normal) Hemoglobin < 8 gm/dL or dependent upon transfusion to maintain ≥ 8 gm/dL White blood cell count < 2,000/mm3 Platelet count < 100,000/mm3 or dependent upon transfusion to maintain ≥ 100,000 mm3 Creatinine > 2.0 times the upper limit of normal or calculated creatinine clearance ≤ 40 mL/min.
12. Pregnant or lactating females.
13. Prior solid organ transplantation
14. Patients who, in the opinion of the Investigator, will be non-compliant with study schedules or procedures.
15. Patients who belong to a vulnerable population such as the homeless, the developmentally disabled and prisoners or have any condition that impairs their ability to provide informed consent or comply with study schedules or procedures.
16. Patients with documented anaphylaxis as a result of penicillin allergy.

• David Bartlett, MD, Principal investigator, Allegheny Health Network