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Nevus

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Pembrolizumab

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Fludarabine phosphate

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Alkylating Agents

Antineoplastic Agents, Immunological

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Six patients will be included in Part A. After inclusion 300 mL blood will be drawn from the patients for the production of the MASE-T cell product. Four days prior to MASE-T infusion the patient will receive lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v. on day -4, -3) followed by i.v. infusion of the MASE-T product on day 0.

Six patients will be includede in Part B. After inclusion 300 mL blood will be drawn from the patients for the production of the MASE-T cell product. Four days prior to MASE-T infusion the patient will receive lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v on day -4, -3) followed by i.v infusion of the MASE-T product on day 0. Pembrolizumab 2 mg/kg will be administered on day -1 and day +21.

Cyclophosphamide 500 mg/m2 is administered i.v. on day -4, -3 and -2

Fludarabine Phosphate 30 mg/m2 is administered on day -4 and -3

Fludarabine Phosphate

Antigen specific, ex vivo expanded T cells derived from peripheral blood T cells

Multiple Antigen Specific Endogenously derived T cells

Pembrolizumab 2 mg/kg is administered on day -1 and on day 21. The medicine is administered over 30 minutes

Inge M Svane, Prof, M.D.

Tine J Monberg, M.D.

Tine J Monberg, MD

Inge M Svane, Prof., M.D.

With the introduction of checkpoint inhibitors substantial improvements have been made in the treatment of malignant melanoma (MM). Despite this still a a subset of patients, approximately 50 %, experience no response to therapy.

One of the strategies to overcome these obstacles have been ACT with tumour infiltrating lymphocytes (TILs). Most TIL based ACT products are non-specifically expanded providing growth preference to co-infiltrated virus specific T cells, and it is currently challenging to expand T cells in an antigen-specific manner, while at the same time obtaining the ideal functional characteristics for specific and strong tumour-killing capacity with sufficient persistence.

In this phase I trial artificial antigen-presenting scaffolds for antigen-driven T cell expansion are used. These scaffolds will generate a MASE-T cell product enriched for selected specificities towards antigens known to be expressed by melanoma cells The aim of the study is to demonstrate that treatment with af MASE-T cell product i safe and feasible. Further the study will elucidate whether treament with the MASE-T cell product leads to objective responses and improves progression free survival (PFS).

There are around 350-400 new cases of patients with metastatic melanoma (MM) per year in Denmark. MM is a very aggressive cancer with a poor prognosis. Traditional oncological treatments such as surgery, chemotherapy and radiation therapy have a poor effect, and the 5-year overall survival has hitherto been less than 10 %.Substantial improvements have been made in the treatment of MM; especially immunotherapy is showing promising results with checkpoint inhibitors (CPI) such as programmed cell death protein 1 (PD-1) and Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA-4) blocking antibodies administered as standard treatment in the frontline. The 5-year overall survival has now reached 52 %, 44 % and 26 % in nivolumab/ipilimumab, nivolumab, and ipilimumab respectively. However, a subset of patients - approximately 50 % experience no response to therapy, with clear primary resistance. One of the strategies to overcome these obstacles have been ACT with tumour infiltrating lymphocytes (TILs). A crucial condition for optimal ACT based on TILs is the generation of sufficient numbers of tumourreactive T cells. However, the expansion of TILs requires extensive ex vivo culturing often at the cost of T cell differentiation and functional activity. Most TIL based ACT products are non-specifically expanded providing growth preference to co-infiltrated virus specific T cells, and it is currently challenging to expand T cells in an antigen-specific manner, while at the same time obtaining the ideal functional characteristics for specific and strong tumour-killing capacity with sufficient persistence. Recent data suggest that the majority of tumour specific T cells responsible for tumour rejection under CPI are recruited from peripheral blood and lymph system, while not present in the tumour prior to treatment. This is supported by the finding that most tumour resident T cells are dysfunctional.

To overcome the current limitations in the treatment of malignant melanoma artificial antigen-presenting scaffolds for antigen-driven T cell expansion, generating a MASE-T cell product enriched for selected specificities towards antigens known to be expressed by melanoma cells has been designed. The antigen-scaffolds will ensuring optimal T cell stimulation by mimicking the in vivo stimulation of T cells by dendritic cells in the lymph nodes. The scaffolds contain both the antigen specific element - in the form of a peptide-MHC molecule and cytokine (IL2 and IL21), to provide growth and functional signals to the antigen specific T cell. As a result of this T cell expansion strategy, we can obtain a T cell product enriched for tumourantigen specific T cells. Superior functional activity towards tumor cells and antigen recognition compared to conventional T cell expansion strategies has been demonstrated in-vitro. Importantly, antigen-specific T cells in the MASE-T cell product possess a 'younger' phenotype, which has previously been described to correlate with improved in vivo persistence.

The study is a phase 1, non-randomized study. The trial will be conducted in two parts (A and B). Patients will be treated as followed:

* Part A (6 patients): Lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v. on day -4, -3) followed by i.v. infusion of the MASE-T product on day 0. If the production of the MASE-T cell product was feasible for the majority (≥50%) of patients intended to treat in Arm A and the toxicity was acceptable, six patients will further be included in part B.
* Part B (6 patients): Lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v on day -4, -3) followed by i.v infusion of the MASE-T product on day 0. Pembrolizumab 2 mg/kg will be administered on day -1 and day +21.

The primary objective is to evaluate the safety and feasibility of the MASE-T treatment alone or in combination with Pembrolizumab in patients with stage IV metastatic melanoma according to Common Terminology Criteria for Adverse Events (CTCAE version 5.0).

The secondary objectives are to evaluate T cell profile and persistence in vivo from tumor biopsies and blood samples as well as evaluation of the clinical efficacy of the treatment according to RECIST 1.1 and iRECIST. In addition, best overall response (BOR), duration of response (DOR), overall survival (OS), progression-free survival (PFS) will be monitored.

12 Patients will be indluced in two steps.

* Part A (6 patients): Lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v. on day -4, -3) followed by i.v. infusion of the MASE-T product on day 0. If the production of the MASE-T cell product was feasible for the majority (\>50%) of patients intended to treat in Arm A and the toxicity was acceptable, six patients will further be included in part B.
* Part B (6 patients): Lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2/day i.v. on day -4, -3, -2 and fludarabine 30 mg/m2/day i.v on day -4, -3) followed by i.v infusion of the MASE-T product on day 0. Pembrolizumab 2 mg/kg will be administered on day -1 and day +21.

ImmPACT Expanded Multiple Antigen Specific Endogenously Derived T Cells (MASE-T) to Patients With Metastatic Melanoma

Adoptive Transfer of ImmPACT Expanded Multiple Antigen Specific Endogenously Derived T Cells (MASE-T) in Combination With Lymphodepletion and Anti-PD-1 to Patients With Metastatic Melanoma

Fraction of patients experiencing grade III or worse adverse events

Number of patients excluded due to treatment related feasibility issues compared to the number of patients enrolled in the study.

Number of patients excluded due to treatment related safety issues compared to the number of patients enrolled in the study.

Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) assessed by CT scan.

Spots Global Cancer Trial Database for multiple antigen specific endogenously derived t cells