Background:
The presence of T-lymphocytes in resected tumor samples derived from long-term survival patients and the fact that reinvigoration of their functionality through the administration of specific immune-therapies can lead to remarkable antitumor responses supports that lymphocytes play a critical role in cancer immunity.
Adoptive cell therapy using tumor-infiltrating lymphocytes product (TIL-ACT) is a well-established combination therapy currently under study in several world reference centers, using an autologous cell product without genetic modifications. This cell product consists of tumor-infiltrating lymphocytes (TIL), which are collected from the patient and expanded in the lab under specific conditions to enhance its antitumoral efficacy before reinfusion in the same patient. However, this cell product alone does not achieve adequate efficacy, and a combination of both previous non-myeloablative lymphodepleting (NMA-LD) chemotherapy and subsequent cytokine therapy (specifically IL-2) is needed to support the expansion of the infused cells.
The investigators hypothesize that TILs enriched for neoantigen recognition are superior to unselected TILs at mediating tumor regression in patients with epithelial tumors and even other solid tumors where immune checkpoint blockade (ICB) is approved and used as part of standard therapy. The investigators propose to manufacture a T-cell product composed of TILs that are selected based on their ability to recognize patient-specific neoantigens and to use these to treat patients with metastatic, refractory, epithelial cancers, as well as ICB-resistant solid tumors. Furthermore, it also proposed to study the tumor and T cells at baseline and after treatment to investigate whether specific phenotypic and functional traits may be associated with clinical outcome.
Primary objective:
To evaluate the safety and the tolerability of ex vivo next generation neoantigen-selected Tumor-infiltrating Lymphocyte (TIL) in patients with metastatic or unresectable epithelial tumors and immune checkpoint blockade (ICB) resistant solid tumors.
Secondary objectives:
* To determine the success in producing active specific TILs from our target patients. * To evaluate the initial clinical activity of the NEXTGEN-TIL products in our target patients.
Patients must have histologically or cytologically proven metastatic or unresectable solid tumors. The disease must have progressed to at least one standard therapy (including at least one prior line with ICB for the group of patients with tumors where ICB is approved), or the patient is unable/unwilling to receive standard therapy or no standard therapy exists for a particular disease.
Patients must have at least one adequate lesion (primary tumor or metastasis) for resection or biopsy for TIL generation with minimal morbidity (preferentially using imaging-guided minimally invasive procedures).
Patient must be at least 18 years old at the tissue procurement visit.
Patient must understand and voluntarily sign an informed consent document before any study-related assessments/procedures being conducted.
Patients with symptomatic and/or untreated brain metastases. Note: Patients with definitively-treated brain metastases will be considered for enrollment after discussion with Medical Monitor; if, prior to the start of NMA-LD the patient is clinically stable for ≥3 months, there are no new brain lesions via magnetic resonance imaging (MRI) post-treatment, and the patient does not require corticosteroid treatment >10 mg prednisone or equivalent per day.
Patients with leptomeningeal carcinomatosis.
Patients with an active concurrent or history within the past 3 years of invasive malignancy, except for non-melanoma skin cancer, cervical and bladder carcinoma in situ, good prognosis ductal carcinoma in situ of the breast, or prostate carcinoma that is in remission under androgen deprivation therapy for > 2 years. Other exceptions may apply and require discussion between the Investigator and the Medical Monitor.
Patients with an active systemic infection requiring anti-infective treatment within 14 days before preparative lymphodepleting therapy.
Single group
NEXTGEN-TIL
Biological/VaccineNEXTGEN-TIL product is a cellular investigational product comprising a live cell suspension of autologous tumor-infiltrating lymphocytes derived from the patient's own tumor. Each dose contains at least 5 x 10\^8 total viable lymphocytes, and a maximum of 1.11x10\^11. It will be administered IV on Day 0 (24h after the last dose of Fludarabine).
Non-myeloablative Lymphodepletion (NMA-LD) Regimen
DrugPatients will receive a NMA-LD chemotherapy based on Cyclophosphamide 60 mg/kg IV (once daily on Days -5 and -4) and Fludarabine 25 mg/m2 IV (once daily on Days -5 to -1).
Interleukin-2
DrugPatients will receive sequential doses of 720,000 IU/kg IV IL-2 every 8-24 hours depending on patient tolerance. It will be administered on Days 0 to 2, starting between 3 and 24 hours after the completion of NEXTGEN-TIL infusion. IL-2 doses may be skipped in case of toxicity. If 2 sequential doses or more than 2 non-sequential doses of IL-2 are skipped due to patient intolerance or the discretion of the investigator, IL-2 administration must be stopped.
Incidence of Adverse Events (AE)
Nature and frequency of AE, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Incidence of Serious Adverse Events (SAE)
Nature and frequency of SAE, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Treatment-limiting Toxicity (TLT)
Toxicities related to treatment administration that, if recurrent at high enough frequency (≥2 patients treated), should trigger review by the Independent Data Safety Monitoring Board (IDSMB), which could lead to recommendations for treatment modifications for subsequent patients.
Incidence of alterations in clinical laboratory test results
Nature and frequency of abnormalities found in clinical laboratory test results
Neoantigen-selected TIL analysis
Rate of successful neoantigen-selected TIL (NEXTGEN-TIL) generation from biopsied patients and frequency of neoantigen-specific TILs in all TILs produced from biopsied patients included in this trial.
Overall Response Rate (ORR)
ORR per RECIST v1.1 as assessed by investigator, defined as proportion of patients who have a partial or complete response to therapy.
Duration of Response (DOR)
DOR per RECIST v1.1 as assessed by investigator, defined as the time elapsed between the initial response to therapy and subsequent disease progression or relapse.
Progression-Free Survival (PFS)
PFS per RECIST v1.1 as assessed by investigator, defined as the time from the date of treatment administration to the date of first documentation of disease progression or death due to any cause, whichever occurs first. For a patient who has not progressed and is last known to be alive, PFS will be censored at the last response assessment that is stable disease (SD) or better.
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Vall d'Hebron Institute of Oncology
Lead sponsor
Banc de Sang i Teixits
Collaborator
