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Subjects will receive a therapy based on Tumor-infiltrating Lymphocyte (NEXTGEN-TIL product) preceded by a preparative non-myeloablative lymphodepleting (NMA-DL) regimen and followed by IL-2 infusion. Patients will be followed-up for 2 years, assessed at weeks 2, 3, 4, 6, 9, 12, 18, 24, 30, 36 (9 months), and then at 1 year, 1,5 and 2 years.

NEXTGEN-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).

NEXTGEN-TIL

Patients 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).

Non-myeloablative Lymphodepletion (NMA-LD) Regimen

Patients 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.

Elena Garralda

Susana Muñoz

Elena Garralda, MD

Vladimir Galvão de Aguiar, MD

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.

Methods:

This study is a first-in-human, open-label, non-controlled, single-centre, phase I trial to assess the safety and tolerability of NEXTGEN-TIL-ACT. Given the exploratory nature of the study, there is no formal hypothesis testing and no formal sample size calculation was carried out.

A sample size of 10 patients has been selected to provide information about the frequency of treatment-limiting toxicity (TLT).

Study treatment:

The main study therapy is the Tumor-infiltrating Lymphocyte (NEXTGEN-TIL) product, which is preceded by a preparative non-myeloablative lymphodepleting (NMA-DL) regimen and followed by IL-2 infusion.

NEXTGEN-TIL product is a cellular investigational product comprising a live cell suspension of autologous tumor-infiltrating lymphocytes derived from the patient's own tumor.

First-in-human, open-label, non-controlled, single-centre, phase I trial. Sequential recruitment: The first six patients will be included for safety assessment. If no more than one treatment-limiting toxicity (TLT) is observed, four additional patients will be included for the final safety population analysis (a total of 10 patients).

Assessment of the Safety and Tolerability of ex Vivo Next-generation Neoantigen-selected Tumor-infiltrating Lymphocyte (TIL) Therapy in Advanced Epithelial Tumors and Immune Checkpoint Blockade (ICB) Resistant Solid Tumors

A Phase I Study to Assess the Safety and Tolerability of ex Vivo Next-generation Neoantigen-selected Tumor-infiltrating Lymphocyte (TIL) Therapy in Advanced Epithelial Tumors and Immune Checkpoint Blockade (ICB) Resistant Solid Tumors

Nature and frequency of AE, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Nature and frequency of SAE, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

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.

Nature and frequency of abnormalities found in clinical laboratory test results

Nature and frequency of abnormalities found in electrocardiogram

Nature and frequency of abnormalities found in vital signs.

Nature and frequency of abnormalities found in the physical examination.

Patient performance status assessed as per Eastern Cooperative Oncology Group (ECOG) score, where grade 0 is for fully active and capable patient and grade 5 is death.

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.

ORR per RECIST v1.1 as assessed by investigator, defined as proportion of patients who have a partial or complete response to therapy.

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.

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.

Spots Global Cancer Trial Database for immune checkpoint blockade resistant tumors