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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A recombinant form of IL-2 (aldesleukin, Proleukin™) is the only interleukin approved for cancer therapy and is licensed to treat metastatic renal cell carcinoma. However, the response rate is less than 50%, and it causes capillary leakage leading to hypotension and pulmonary edema which limits its use. Interleukin-1 (IL-1) has also been shown to possess both direct and indirect antitumor effects, and has been investigated for its ability to protect bone marrow cells from the deleterious effects of radiation and chemotherapy. Studies are also underway to determine whether IL-2 can enhance the efficacy of cancer vaccines. Since the recombinant cytokine first became available for clinical use, treatment with IL-2 has been evaluated in many different dose ranges, schedules, and routes of administration in attempts to maximize efficacy and minimize toxicity. While only the high-dose IL-2 IV bolus regimen is approved by the FDA, positive results have been seen in clinical trials that administered this agent by continuous intravenous infusion (CIV) at lower doses for up to 90 days. IL-2 is still important in cancer immunotherapeutic trials and, at the time of writing, there are over 70 clinical trials investigating IL-2 as an agent to stimulate and expand T cells or NK cells.
Combinational therapies for the treatment of advanced cervical cancer
Published in Expert Opinion on Pharmacotherapy, 2023
Adoptive T-cell therapy. Adoptive immunotherapy is also studied in advanced cervical cancer. In a small trial with previously treated advanced cervical cancer, patients received adoptive T-cell therapy using isolated and expanded tumor-specific T-cells selected for HPV E6 and E7 reactivity. Expanded T-cells were infused, preceded by non-myeloablative conditioning chemotherapy followed by a high-dose bolus of aldesleukin. Interestingly, one patient with chemotherapy-refractory HPV 16+ squamous cell carcinoma and widespread metastases had a complete response, as did another patient with an HPV 18+ adenocarcinoma refractory to chemoradiation. The complete responses were ongoing at 18 and 11 months, respectively. One more patient achieved a partial response [39]. A second study in patients with HPV-associated cancers yielded responses in 5 out of 18 (28%) patients with cervical cancer and 2 of 11 (18%) noncervical patients. Complete responses were ongoing after 67 and 53 months after treatment in cervical cancer patients [40].
Anti-inflammatory strategies for atherosclerotic artery disease
Published in Expert Opinion on Drug Safety, 2022
Federica Agnello, Davide Capodanno
It is likely that, in the next future, medications aiming at generating an atheroprotective immunity will include a low dose of IL-2, which induces an expansion of Treg cells. The impact of once-daily subcutaneous administration of aldesleukin (i.e. low dose-IL-2) for 5 consecutive days was tested in patients with chronic coronary syndromes (part A, n = 25 patients) and patients with NSTEMI (part B, n = 16 patients) in the LILACS (Low dose interleukin-2 in patients with stable ischemic heart disease and acute coronary syndrome) trial, a randomized, double-blind, placebo-controlled, dose-escalation, phase 1/2 clinical study [92]. The trial concluded that low-dose-IL-2 was safe in all dose groups. In the part B of the study, patients treated with the 1.5 and 2.5 × 106 IU/day doses had median increases in Treg cells of 80.5% (CI 36.2–124.7%, p = 0.003) and 108.3% (CI 55.3–161.3%, p = 0.002), respectively.
Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study
Published in OncoImmunology, 2018
Magnus Pedersen, Marie Christine Wulff Westergaard, Katy Milne, Morten Nielsen, Troels Holz Borch, Lars Grønlund Poulsen, Helle Westergren Hendel, Mia Kennedy, Gillian Briggs, Stacey Ledoux, Trine Jakobi Nøttrup, Pernille Andersen, Thomas Hasselager, Özcan Met, Brad H. Nelson, Marco Donia, Inge Marie Svane
Tumor fragments were processed and TIL expanded according to previously published methods39,40. Briefly, 1–2 mm3 tumor fragments (48 in total) were placed into 24-well plates (Nunc, Roskilde, Denmark) in 2 mL of culture medium (90% RPMI 1640 (Invitrogen), 10% heat inactivated Human AB serum (Sigma-Aldrich, St. Louis, MO, USA) containing 6000 IU/mL of IL-2 (Aldesleukin, Novartis, Basel, Switzerland), Penicillin, Streptomycin and Fungizone (Bristol-Myers Squibb, Lyngby, Denmark). The bulked culture of YT from this initial outgrowth were then either cryopreserved or directly used in a rapid expansion protocol (REP) to generate the final infusion product. Approximately 20 × 106 TIL were used to initiate the REP using a dynamic expansion platform as previously described39. Briefly, 30 ng/ml anti-CD3 antibodies (OKT3, Miltenyi Biotec, Bergisch Gladbach, Germany) were added to the REP culture (TIL in 80/20 medium (80% CM/20% AIM-V medium)) to nonspecifically induce proliferation of the TIL. Irradiated (40 Gy) allogeneic feeder cells (peripheral blood mononuclear cells (PBMC) from at least 4 different healthy donors) at a 1:200 ratio were added to further stimulate TIL growth through secretion of stimulating cytokines. At day 14, TIL were harvested and transferred to a 400 mL infusion bag in a suspension of sodium chloride with 2.5% albumin. Sterility testing and microbiological control were performed on all TIL cultures before REP or cryopreservation and before infusion.