Magnus Pedersen1,2, Marie Christine Wulff Westergaard1, Katy Milne3, Morten Nielsen1,2, Troels Holz Borch1,2, Lars Grønlund Poulsen4, Helle Westergren Hendel5, Mia Kennedy3, Gillian Briggs3, Stacey Ledoux3, Trine Jakobi Nøttrup6, Pernille Andersen7, Thomas Hasselager8, Özcan Met1,2, Brad H Nelson3,9, Marco Donia1,2, Inge Marie Svane1,2. 1. Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. 2. Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. 3. Deeley Research Centre, BC Cancer, Victoria, Canada. 4. Department of Gynecology and Obstetrics, Herlev Hospital, University of Copenhagen, Herlev, Denmark. 5. Department of Clinical Physiology and Nuclear Medicine, Herlev Hospital, University of Copenhagen, Herlev, Denmark. 6. Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 7. Department of Clinical Immunology and Stem Cell Facility, Herlev Hospital, University of Copenhagen, Herlev, Denmark. 8. Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. 9. Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Abstract
Objective:Ovarian cancer (OC) is often diagnosed at an advanced stage with two thirds of patients experiencing recurrent disease with a poor prognosis. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has shown curative potential in malignant melanoma, but has only been investigated scarcely in other cancers. In this pilot study, we tested TIL based ACT in patients with metastatic OC. Methods: Six patients with progressive platinum-resistant metastatic OC were treated with an infusion of TIL preceded by standard lymphodepleting chemotherapy and followed by decrescendo intravenous interleukin-2 (IL-2). Primarily, the feasibility and tolerability of the treatment was assessed. Secondarily, disease control rate was described and immune responses against tumor cells were monitored. Results: Treatment was well tolerated with manageable toxicities. Four patients had stable disease for three months and two patients for five months with five patients having a decrease in target lesions. Progression was primarily due to new lesions while target lesions in general remained stable or in regression. Antitumor reactivity was observed in TIL infusion products from five patients but no antitumor reactivity was detectable in peripheral blood lymphocytes collected after treatment. High numbers of infused TIL expressed exhaustion markers including LAG3 and PD-1, and immunostaining of tumor tissue demonstrated substantial MHCII and PD-L1 expression. Conclusions:ACT with TIL in combination with decrescendo IL-2 is feasible in patients with metastatic OC. Early indications of clinical activity were found. However, TIL ACT efficacy was incomplete with possible involvement of the inhibitory immune checkpoint pathways LAG3/MHCII and PD1/PD-L1.
Objective:Ovarian cancer (OC) is often diagnosed at an advanced stage with two thirds of patients experiencing recurrent disease with a poor prognosis. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has shown curative potential in malignant melanoma, but has only been investigated scarcely in other cancers. In this pilot study, we tested TIL based ACT in patients with metastatic OC. Methods: Six patients with progressive platinum-resistant metastatic OC were treated with an infusion of TIL preceded by standard lymphodepleting chemotherapy and followed by decrescendo intravenous interleukin-2 (IL-2). Primarily, the feasibility and tolerability of the treatment was assessed. Secondarily, disease control rate was described and immune responses against tumor cells were monitored. Results: Treatment was well tolerated with manageable toxicities. Four patients had stable disease for three months and two patients for five months with five patients having a decrease in target lesions. Progression was primarily due to new lesions while target lesions in general remained stable or in regression. Antitumor reactivity was observed in TIL infusion products from five patients but no antitumor reactivity was detectable in peripheral blood lymphocytes collected after treatment. High numbers of infused TIL expressed exhaustion markers including LAG3 and PD-1, and immunostaining of tumor tissue demonstrated substantial MHCII and PD-L1 expression. Conclusions:ACT with TIL in combination with decrescendo IL-2 is feasible in patients with metastatic OC. Early indications of clinical activity were found. However, TIL ACT efficacy was incomplete with possible involvement of the inhibitory immune checkpoint pathways LAG3/MHCII and PD1/PD-L1.
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