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Interleukin 2 (Aldesleukin)

Interleukin 2 (IL-2) is a naturally occurring cytokine made by T-lymphocytes (a type of white blood cell). It stimulates the growth and activity of other T-lymphocytes and B-lymphocytes as part of the immune system. Aldesleukin (Interleukin 2 produced in the laboratory) can be used in the treatment of certain cancers to boost the immune system to help the body fight cancer.

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Web Resources: IL2
Latest Research Publications

Web Resources: IL2 (6 links)

Latest Research Publications

Sullivan RJ
Back to the Future: Rethinking and Retooling IL2 in the Immune Checkpoint Inhibitor Era.
Cancer Discov. 2019; 9(6):694-695 [PubMed] Related Publications
IL2 is a type I cytokine that is associated, when given at high doses intravenously, with durable regressionin a subset of patients with metastatic melanoma and renal cell carcinoma, yet high toxicity limits its use. NKTR-214 is a novel pegylated IL2 with minor clinical activity as a single agent, but a favorable toxicity profile and compelling pharmacodynamic effects that predict utility in combination with immune checkpoint inhibition.

Shokrzadeh M, Mohammadpour A, Hoseini V, et al.
Arq Gastroenterol. 2018 Oct-Dec; 55(4):385-389 [PubMed] Related Publications
BACKGROUND: Gastric adenocarcinoma is the fourth most common cause of cancer-associated death worldwide.
OBJECTIVE: We evaluated the immunological status of patients with gastric cancer before surgery and circulating cytokines as potential diagnostic biomarkers for gastric cancer.
METHODS: We included 90 healthy controls and 95 patients with distal Gastric adenocarcinoma in Mazandaran, Sari, Iran. We measured serum IL-2, IL-10 and IL-12 Levels by a sandwich enzyme-linked immunosorbent assay using the IBL international GMBH kit.
RESULTS: The serum IL-10 levels in the patients with Gastric adenocarcinoma were significantly higher than those of the healthy controls (P=0.02). There were no significant differences in serum IL-2 and IL-12 levels between patients with gastric cancer and healthy controls.
CONCLUSION: Increased levels of IL-10 might be useful as diagnostic biomarkers for Gastric adenocarcinoma; however, this needs to be confirmed with larger number of patients and with control groups other than blood donors, properly age paired. These results suggest that positive expression of IL-10 may be useful as a molecular marker to distinguish stage of gastric cancers which can be more readily controlled.

Nguyen LT, Saibil SD, Sotov V, et al.
Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2.
Cancer Immunol Immunother. 2019; 68(5):773-785 [PubMed] Related Publications
Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vβ chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.).

Cheung LS, Fu J, Kumar P, et al.
Second-generation IL-2 receptor-targeted diphtheria fusion toxin exhibits antitumor activity and synergy with anti-PD-1 in melanoma.
Proc Natl Acad Sci U S A. 2019; 116(8):3100-3105 [PubMed] Free Access to Full Article Related Publications
Denileukin diftitox (DAB-IL-2, Ontak) is a diphtheria-toxin-based fusion protein that depletes CD25-positive cells including regulatory T cells and has been approved for the treatment of persistent or recurrent cutaneous T cell lymphoma. However, the clinical use of denileukin diftitox was limited by vascular leak toxicity and production issues related to drug aggregation and purity. We found that a single amino acid substitution (V6A) in a motif associated with vascular leak induction yields a fully active, second-generation biologic, s-DAB-IL-2(V6A), which elicits 50-fold less human umbilical vein endothelial cell monolayer permeation and is 3.7-fold less lethal to mice by LD

Boyman O, Arenas-Ramirez N
Development of a novel class of interleukin-2 immunotherapies for metastatic cancer.
Swiss Med Wkly. 2019; 149:w14697 [PubMed] Related Publications
Tumour immunotherapy, and particularly immue checkpoint inhibitors, have resulted in considerable response rates in patients with metastatic cancer. However, most of these approaches are limited to immunogenic tumours. Based on its ability to stimulate cytotoxic T cells, interleukin-2 (IL-2) has been used to treat patients with metastatic melanoma and metastatic kidney cancer. Clinical efficacy achieved through high doses is countered by severe adverse effects on vascular endothelial cells and various organs, a short in vivo half-life, and the stimulation of regulatory T cells that counteract antitumour immune responses. Accumulating evidence suggests that IL-2 receptor β (CD122)-biased IL-2 formulations address the shortcomings of IL-2 cancer immunotherapy. This knowledge stems from studies using CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2 complexes), which preferentially stimulate CD8+ T cells, while interaction with regulatory T cells and vascular endothelial cells is disfavoured by the anti-IL-2 antibody used. CD122-biased IL-2 complexes, when assessed in different mouse cancer models, cause stronger antitumour effects and significantly less adverse effects than high-dose IL-2. A recently developed and characterised anti-human IL-2 antibody, termed NARA1, forms human CD122-biased IL-2 complexes. Alternative strategies based on this concept, such as site-directed pegylation and mutation of IL-2, have also been pursued. Moreover, recent data have shown that a combination of CD122-biased IL-2 formulations with immune checkpoint inhibitors, antigen-specific immunotherapy and epigenetic modifying drugs results in synergistic anti-cancer effects in various tumour models. Thus, CD122-biased IL-2 approaches constitute a novel class of immunotherapy for metastatic cancer that has the potential to complement and increase the efficacy of other antitumour strategies.

McQuade JL, Homsi J, Torres-Cabala CA, et al.
A phase II trial of recombinant MAGE-A3 protein with immunostimulant AS15 in combination with high-dose Interleukin-2 (HDIL2) induction therapy in metastatic melanoma.
BMC Cancer. 2018; 18(1):1274 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: HDIL-2 is approved for advanced melanoma based on its durable antitumor activity. MAGE-A3 cancer immunotherapeutic (MAGE-A3 CI) is a recombinant MAGE-A3 protein combined with an immunostimulant adjuvant system and has shown antitumor activity in melanoma. We assessed the safety and anti-tumor activity of HDIL-2 combined with MAGE-A3 CI in advanced melanoma.
METHODS: Patients with unresectable Stage III or Stage IV MAGE-A3-positive melanoma were enrolled in this phase II study. Treatment included an induction phase of MAGE-A3 CI plus HDIL-2 for 8 cycles followed by a maintenance phase of MAGE-A3 CI monotherapy. The primary endpoints were safety and objective response assessed per RECIST v1.1. Immune biomarker and correlative studies on tumor and peripheral blood were performed.
RESULTS: Eighteen patients were enrolled. Seventeen patients were evaluable for safety and sixteen for response. Responses occurred in 4/16 (25%) patients with 3 complete responses, and stable disease in 6/16 (38%) patients with a disease control rate of 63%. The median duration of response was not reached at median follow-up of 36.8 months. Induction therapy of HDIL-2 + MAGE-A3 CI had similar toxicities to those reported with HDIL-2 alone. Maintenance MAGE-A3 monotherapy was well-tolerated. Increased immune checkpoint receptor expression by circulating T regulatory cells was associated with poor clinical outcomes; and responders tended to have increased tumor infiltrating T cells in the baseline tumor samples.
CONCLUSIONS: The safety profile of HDIL-2 + MAGE-A3 CI was similar to HDIL-2 monotherapy. Maintenance MAGE-A3 CI provides robust anti-tumor activity in patients who achieved disease control with induction therapy. Immune monitoring data suggest that MAGE-A3 CI plus checkpoint inhibitors could be a promising treatment for MAGE-A3-positive melanoma.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT01266603 . Registered 12/24/2010, https://clinicaltrials.gov/ct2/show/NCT01266603.

Hu S, Chen CW, Chen ST, et al.
Inhibitory effect of berberine on interleukin-2 secretion from PHA-treated lymphocytic Jurkat cells.
Int Immunopharmacol. 2019; 66:267-273 [PubMed] Related Publications
Berberine is an isoquinoline alkaloid isolated from herb plants, such as Cortex phellodendri (Huangbai) and Rhizoma coptidis (Huanglian). Huanglian and Huangbai have been used as "heat-removing" agents. In addition, berberine has been reported to exert anti-inflammatory effect both in vivo and in vitro, where mitogen-activated protein kinase (MAPK) and cyclooxygenase-2 (COX-2) expressions are critically implicated. We herein tested the hypothesis that berberine exerts an anti-inflammatory effect through MAPK and COX-2 signaling pathway in T-cell acute lymphoblastic leukemia (T-ALL). In Jurkat cells, we found that PHA exposure caused elevation on interleukin-2 (IL-2) production in a time-dependent manner. PHA-stimulated reactions were steeply suppressed by berberine, such as IL-2 mRNA expression and protein secretion. However, berberine did not exert any cytotoxic effect at doses of 40 μg/ml. In addition, the possible molecular mechanism of anti-inflammation effect of berberine could be the inhibition of PHA-evoked phosphorylation of p38, since c-Jun N-terminal kinases (JNK) and extracellular signal-regulated kinase (ERK) expressions did not alter. Consistent with above results, berberine inhibition on PHA-induced IL-2 secretion could be reversed by treatment of SB203580, a specific inhibitor of p38-MAPK. Interestingly, upregulation of PHA-induced COX-2 expression was also observed following berberine treatment of Jurkat cells. Furthermore, flow cytometry analysis showed berberine-induced cell cycle arrest at G1 phase after PHA stimulation and decreased percentage of G2/M phase. In conclusion, our study demonstrated that the anti-inflammatory effect of berberine largely potentially results from its ability to attenuate p38 MAPK expression, and does not exclude a positive action of berberine on cell cycle arrest. These results provide an innovative medicine strategy to against or treat T-ALL patients.

Zhang L, Li S, Wang R, et al.
Cytokine augments the sorafenib-induced apoptosis in Huh7 liver cancer cell by inducing mitochondrial fragmentation and activating MAPK-JNK signalling pathway.
Biomed Pharmacother. 2019; 110:213-223 [PubMed] Related Publications
Sorafenib is a standard targeted drug used to treat hepatocellular carcinoma (HCC). Notably, cytokine has been found to further enhance the therapeutic effectiveness of the targeted drug. Thereby, the aim of this study is to verify whether cytokine IL-2 could increase the anti-cancer effects of sorafenib on liver cancer in vitro. Huh7 cells were used in the present study and the cell apoptosis and migration were determined in response to sorafenib treatment. Then, siRNA and pathway blocker were used to determine the molecular mechanisms by which IL-2 enhance the therapeutic effectiveness of Huh7 liver cancer cell in vitro. The data in our study illustrated that sorafenib treatment induced apoptosis in Huh7 liver cancer cell in vitro, an effect that was accompanied with a drop in cell proliferation and migration. Biological investigation demonstrated that IL-2 supplementation further augmented the pro-apoptotic effects of sorafenib in vitro. At the molecular levels, the combination of IL-2 and sorafenib impaired mitochondrial respiratory function, reduced mitochondrial potential, promoted mitochondrial ROS overloading and activated mitochondrial apoptotic pathway. Meanwhile, we found that IL-2 supplementation induced mitochondrial stress via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. Blockade of the JNK signalling pathway and/or knockdown of TAZ could abrogate the inhibitor effects of IL-2/sorafenib on liver cancer survival, growth and mobility. Collectively, these data indicated that IL-2 supplementation could further augment the anti-cancer effectiveness of sorafenib via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. This finding identifies mitochondrial stress and the JNK-Hippo pathway as the potential targets to treat liver cancer.

Ladenstein R, Pötschger U, Valteau-Couanet D, et al.
Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial.
Lancet Oncol. 2018; 19(12):1617-1629 [PubMed] Related Publications
BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma.
METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m
FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192).
INTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available.
FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.

Benonisson H, Sow HS, Breukel C, et al.
High FcγR Expression on Intratumoral Macrophages Enhances Tumor-Targeting Antibody Therapy.
J Immunol. 2018; 201(12):3741-3749 [PubMed] Related Publications
Therapy with tumor-specific Abs is common in the clinic but has limited success against solid malignancies. We aimed at improving the efficacy of this therapy by combining a tumor-specific Ab with immune-activating compounds. In this study, we demonstrate in the aggressive B16F10 mouse melanoma model that concomitant application of the anti-TRP1 Ab (clone TA99) with TLR3-7/8 or -9 ligands, and IL-2 strongly enhanced tumor control in a therapeutic setting. Depletion of NK cells, macrophages, or CD8

Qian J, Fang D, Lu H, et al.
Tanshinone IIA promotes IL2-mediated SW480 colorectal cancer cell apoptosis by triggering INF2-related mitochondrial fission and activating the Mst1-Hippo pathway.
Biomed Pharmacother. 2018; 108:1658-1669 [PubMed] Related Publications
IL-2-based therapy is a promising tool to treat colorectal cancer, but drug resistance always occurs in clinical practice. Mitochondrial fission is a novel target to modulate cancer development and progression. The aim of our study is to explore the effect of IL-2 combined with Tan IIA on SW480 colorectal cancer cell apoptosis in vitro and to determine whether IL-2/Tan IIA cotreatment could reduce SW480 cell viability via activating mitochondrial fission. The results indicated that Tan IIA increased IL-2-mediated cell death in SW480 colorectal cancer cells, and this effect was also accompanied with a reduction in cell proliferation. Functional investigations demonstrated that Tan IIA/IL-2 cotreatment enhanced INF2-related mitochondrial fission. Excessive mitochondrial division induced mitochondrial oxidative stress, mitochondrial energy metabolism disorder and mitochondrial apoptosis in SW480 cells. Inhibition of mitochondrial fission attenuated the antitumor effect of Tan IIA/IL-2 cotreatment on SW480 cell apoptosis. Further, we demonstrated that Tan IIA/IL-2 combination therapy controlled INF2-related mitochondrial fission via the Mst1-Hippo pathway. Moreover, Mst1 knockdown abrogated Tan IIA/IL-2-activated mitochondrial fission. Altogether, our results demonstrated that Tan IIA enhances the therapeutic efficiency of IL-2-mediated SW480 colorectal cancer cell apoptosis via promoting INF2-related mitochondrial fission and activating the Mst1-Hippo pathway.

Khong B, Lawson BO, Ma J, et al.
Rigor prophylaxis in stage IV melanoma and renal cell carcinoma patients treated with high dose IL-2.
BMC Cancer. 2018; 18(1):1007 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Rigors are a significant adverse event during interleukin-2 (IL2) therapy for metastatic melanoma and renal cell carcinoma. Meperidine has been a mainstay for rigor prophylaxis but there is a paucity of data regarding possible alternatives.
METHODS: Ninety one patients receiving IL2 therapy for metastatic renal cell carcinoma and melanoma at Huntsman Cancer institute (HCI), Utah from May 2009 to October 2016 were retrospectively evaluated for rigor prophylaxis. Forty two patients received meperidine and 49 received tramadol. Rigors were tabulated using the proxy of number of doses of as needed (PRN) rigor medications and normalized by IL2 doses. Other outcomes of fever, hypotension, and renal insufficiency were noted on a binary scale and normalized by cycles. Statistical analysis was performed utilizing univariate and multivariate negative binomial models.
RESULTS: Ninety one patients were identified with metastatic melanoma or RCC who received high dose IL2 therapy. Forty two received meperidine and 49 received tramadol prophylaxis for rigors. Univariate negative binomial analysis shows incidence rate ratios (IRR): fever 0.41 (95% CI 0.28-0.62, p-value < 0.001), hypotension 1.7 (95% CI 1.11-2.61, p-value 0.015), renal insufficiency 0.58 (95% CI 0.35-0.98, p-value 0.041), rigors per all PRN meds 1.01 (95% CI 0.79-1.28, p-value 0.964), and rigors via opioid PRN meds 0.85 (95% CI 0.67-1.07, p-value 0.168). Multivariate negative binomial analysis shows IRR: fever 0.59 (95% CI 0.28-1.24, p-value 0.163), hypotension 0.93 (95% CI 0.43-2.03, p-value 0.864), renal insufficiency 1.1 (95% CI 0.52-2.32, p-value 0.807), rigors per al PRN meds 0.92 (95% CI 0.67-1.26, p-value 0.604), and rigors via opioid PRN 0.9 (95% CI 0.65-1.26, p-value 0.554).
CONCLUSION: Univariate models indicated meperidine pre-treatment was associated with significantly lower rates of fever and renal insufficiency whereas tramadol was associated with significantly lower rate of hypotension. However, when controlled for demographics and other treatment differences, these differences were no longer significant.

León K, García-Martínez K, Carmenate T, Rojas G
Combining computational and experimental biology to develop therapeutically valuable IL2 muteins.
Semin Oncol. 2018; 45(1-2):95-104 [PubMed] Related Publications
High-dose IL2, first approved in 1992, has been used in the treatment of advanced renal cell carcinoma and melanoma. In these indications, IL2 induces long lasting objective responses in 5% to 20% of patients. However, toxicity and the unexpected expansion of regulatory T cells (Tregs) have limited its practical use and therapeutic impact, respectively. At the Center of Molecular Immunology in Havana, Cuba, a project was launched in 2005 to rationally design IL2 muteins that could be deployed in the therapy of cancer. The basic goal was to uncouple the pleiotropic effect of IL2 on different immune T cells, to obtain a mutein with a therapeutic index that was better than that achieved with wild type (wt) IL2. Using a combination of computational and experimental biology approaches, we predicted and developed two novel IL2 muteins with therapeutic potential. The first, designated no-alpha mutein, is an agonist of IL2R signaling with a reduced ability to expand Treg in vivo. In mice, the no-alpha mutein IL2 has higher antitumor activity and lower toxicity than wt IL2. It represents a potential best-in-class drug that has begun phase I/II clinical trials in solid tumors. The second, designated no-gamma mutein, is an antagonist of IL2R signaling, with some preferential affinity for Tregs. This mutein has antitumor activity in mice that likely derives from its ability to reduce Treg accumulation in vivo. It represents a first-in-class drug that offers a novel strategy to inhibit Treg activity in vivo.

Bosschieter J, Nieuwenhuijzen JA, Hentschel A, et al.
Value of a Marker Lesion in Non-Muscle-Invasive Bladder Cancer Patients Treated with Interleukin-2 Instillations: A Randomized Controlled Multicentre Trial.
Urol Int. 2019; 102(1):69-76 [PubMed] Related Publications
PURPOSE: To compare the effect of intravesical interleukin-2 (IL-2) instillations with and without a marker lesion on time to recurrence (TTR) in non-muscle-invasive bladder cancer (NMIBC) patients.
METHODS: A prospective randomized, controlled trial was conducted. Patients with multiple non-muscle-invasive tumours were randomized for a complete or incomplete transurethral resection (TURBT), followed by 3 IL-2 instillations. The primary end point was TTR.
RESULTS: These are the results of an interim analysis, which was performed due to slow accrual after which the study was closed prematurely. Twenty-eight patients were randomized of which 17 were eligible on an intention-to-treat basis. Median TTR or last follow-up was 3 months (interquartile range [IQR] 3-10 months) for the complete and 4 months (IQR 3-8 months) for the incomplete TURBT group. The TTR between the 2 groups did not differ significantly (log-rank, p = 0.54). -Conclusions: These data do not support the hypothesis that a marker lesion enhances the therapeutic effect of IL-2 instillations in patients with NMIBC.

Kleef R, Moss R, Szasz AM, et al.
Complete Clinical Remission of Stage IV Triple-Negative Breast Cancer Lung Metastasis Administering Low-Dose Immune Checkpoint Blockade in Combination With Hyperthermia and Interleukin-2.
Integr Cancer Ther. 2018; 17(4):1297-1303 [PubMed] Free Access to Full Article Related Publications
The prognosis of triple-negative breast cancer with metastases after chemotherapy remains dismal. We report the case of a 50-year-old female with first disease recurrence at the axillary lymph node and, later on, bilateral pulmonary metastases with severe shortness of breath. The patient received low-dose immune checkpoint blockade (concurrent nivolumab and ipilimumab) weekly over 3 weeks with regional hyperthermia 3 times a week, followed by systemic fever-range hyperthermia induced by interleukin-2 for 5 days. She went into complete remission of her pulmonary metastases with transient WHO I-II diarrhea and skin rash. The patient remained alive for 27 months after the start of treatment, with recurrence of metastases as a sternal mass, and up to 3 cm pleural metastases. This exceptional response should instigate further research efforts with this protocol, which consists only of approved drugs and treatments.

Albertini MR, Yang RK, Ranheim EA, et al.
Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma.
Cancer Immunol Immunother. 2018; 67(10):1647-1658 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Phase I testing of the hu14.18-IL2 immunocytokine (IC) in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m

Bernson E, Hallner A, Sander FE, et al.
Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia.
Cancer Immunol Res. 2018; 6(9):1110-1119 [PubMed] Related Publications
Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML.

Han L, Jiang Q, Yao W, et al.
Thoracic injection of low-dose interleukin-2 as an adjuvant therapy improves the control of the malignant pleural effusions: a systematic review and meta-analysis base on Chinese patients.
BMC Cancer. 2018; 18(1):725 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Interleukin-2 (IL-2) is an important immunotherapy cytokine for various diseases including cancer. Some studies reported the efficacy and safety on cisplatin combined with IL-2 versus cisplatin alone for treating malignant pleural effusion (MPE) through thoracic injection.
METHODS: We searched these studies from medical electronic database. A total of 18 studies that met the inclusion criteria were recruited in this meta-analysis. Pooled odds ratios (OR) with 95% confidence intervals (CI) were determined by the fixed effects model of meta-analysis.
RESULTS: The objective response rate (ORR) and disease control rate (DCR) of cisplatin plus IL-2 for controlling MPE was significantly higher than that of cisplatin alone (p < 0.001). In addition, compared with cisplatin alone, the presence of IL-2 improved the quality of life (QOL) of patients with MPE (p < 0.001). Although the use of IL-2 seemed to increase the probability of fever in patients (p = 0.001), it did not lead to extra other side effects (AEs) including myelotoxicity, nausea/vomiting and chest pain (p > 0.05).
CONCLUSIONS: The low-dose IL-2 improved the ORR, DCR and QOL of patients in the treatment of MPE. Although it may cause fever in patients, it did not increase other AEs.

Choudhry H, Helmi N, Abdulaal WH, et al.
Prospects of IL-2 in Cancer Immunotherapy.
Biomed Res Int. 2018; 2018:9056173 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
IL-2 is a powerful immune growth factor and it plays important role in sustaining T cell response. The potential of IL-2 in expanding T cells without loss of functionality has led to its early use in cancer immunotherapy. IL-2 has been reported to induce complete and durable regressions in cancer patients but immune related adverse effects have been reported (irAE). The present review discusses the prospects of IL-2 in immunotherapy for cancer.

Taylor ES, McCall JL, Shen S, et al.
Prognostic roles for IL-2-producing and CD69
Int J Cancer. 2018; 143(8):2008-2016 [PubMed] Related Publications
Tumor infiltrating T cells are a predictor of patient outcome in patients with colorectal cancer (CRC). However, many T cell populations have been associated with both poor and positive patient prognoses, indicating a need to further understand the role of different T cell subsets in CRC. In this study, the T cell infiltrate from the tumor and nontumor bowel (NTB) was examined in 95 CRC patients using flow cytometry and associations with cancer stage and disease recurrence made. Our findings showed that IFN-γ-producing T cells were associated with positive patient outcomes, and CD69

Nakase K, Kita K, Katayama N
IL-2/IL-3 interplay mediates growth of CD25 positive acute myeloid leukemia cells.
Med Hypotheses. 2018; 115:5-7 [PubMed] Related Publications
Cell surface interleukin-2 receptor α-chain (IL-2Rα, CD25) expression is currently recognized to be a strong predictor for poor prognosis in patients with acute myeloid leukemia (AML). However, it is still unknown that the reason why CD25 positive AML patients have a dismal clinical outcome. CD25 positive AML cells are generally unresponsive to IL-2, but strongly respond to IL-3. The levels of IL-3Rα on these AML cells are very high and directly proportional to the CD25 levels. T-lymphocytes produce IL-3 in response to stimuli including IL-2-mediated activation. Thus, CD25 on AML cells may capture environmental IL-2 and deliver it to the surrounding T-lymphocytes expressing IL-2Rβ/γc, leading to the production of IL-3 as a growth stimulus to CD25 positive AML cells. We hypothesize that IL-2/IL-3 interplay via CD25 is responsible for the growth property of CD25 positive AML, which may affect clinical behavior of those patients.

Singh PK, Kumar V, Ahmad MK, et al.
Association of -330 interleukin-2 gene polymorphism with oral cancer.
Indian J Med Res. 2017; 146(6):730-737 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Background & objectives: Cytokines play an important role in the development of cancer. Several single-nucleotide polymorphisms (SNPs) of cytokine genes have been reported to be associated with the development and severity of inflammatory diseases and cancer predisposition. This study was undertaken to evaluate a possible association of interleukin 2 (IL-2) (- 330A>C) gene polymorphisms with the susceptibility to oral cancer.
Methods: The SNP in IL-2 (-330A>C) gene was genotyped in 300 oral cancer patients and in similar number of healthy volunteers by polymerase chain reaction (PCR)-restriction fragment length polymorphism and the association of the gene with the disease was evaluated.
Results: IL-2 (-330A>C) gene polymorphism was significantly associated with oral cancer whereas it was neither associated with clinicopathological status nor with cancer pain. The AC heterozygous genotype was significantly associated with oral cancer patients as compared to controls [odds ratio (OR): 3.0; confidence interval (CI): 2.14-4.20; P<0.001]. The C allele frequency was also significantly associated with oral cancer (OR: 1.80; CI: 1.39-2.33; P<0.001). IL-2 (-330A>C) gene polymorphism was also associated with oral cancer in tobacco smokers and chewers.
Interpretation & conclusions: Our results showed that oral cancer patients had significantly higher frequency of AA genotype but significantly lower frequency of AC genotype and C allele compared to controls. The IL-2 AC genotype and C allele of IL-2 (-330A>C) gene polymorphisms could be potential protective factors and might reduce the risk of oral cancer in Indian population.

Wang YL, Peng HH, Su SY, Lin CT
Combined Immunotherapy (OK-432, IL-2) With Chemotherapy Decrease the Recurrence Rate in Advanced Ovarian Cancer.
Reprod Sci. 2019; 26(2):244-249 [PubMed] Related Publications
OBJECTIVE: In advanced ovarian cancer, traditional therapy included debulking surgery and postoperative chemotherapy. We proposed immunochemotherapy (IMCT) combined with picibanil (OK-432), interleukin-2 (IL-2), and traditional platinum- and taxol-based chemotherapy as a better treatment option for advanced ovarian cancer.
METHODS: We retrospectively reviewed the medical records of 51 patients with advanced ovarian cancer between 2007 and 2015 at Chang Gung Memorial Hospital Linkou Medical Center, including 26 patients who were treated with OK-432, IL-2, and platinum- and taxol-based chemotherapy (IMCT group) after debulking surgery; another 25 were treated with traditional platinum- and taxol-based chemotherapy (traditional chemotherapy group) after debulking surgery. We analyzed the difference in age, follow-up period, recurrence rate, and diagnosis-to-recurrence period between the 2 groups. We also analyzed the difference in complete blood cell counts, differentiating counts, and cancer antigen 125 (CA-125) at 1 month after treatment.
RESULTS: The recurrence rate between the IMCT and traditional chemotherapy groups showed a significant difference (53.8% vs 88%; P = .0128). The diagnosis-to-recurrence duration was longer in the IMCT than in the traditional chemotherapy groups (33.21 vs 25.63 months), although no statistical significance was found ( P = .4668). In laboratory analysis at 1 month after treatment, the white blood cell, absolute neutrophil, and absolute lymphocyte counts (ALCs) were significantly higher in the IMCT group. On the other hand, CA-125 was significantly lower, and ALC was significantly higher in the nonrecurrence group.
CONCLUSIONS: Combined IMCT and chemotherapy have lower recurrence rate compared to traditional chemotherapy after debulking surgery for the treatment of advanced ovarian cancer.

Carmenate T, Ortíz Y, Enamorado M, et al.
Blocking IL-2 Signal In Vivo with an IL-2 Antagonist Reduces Tumor Growth through the Control of Regulatory T Cells.
J Immunol. 2018; 200(10):3475-3484 [PubMed] Related Publications
IL-2 is critical for peripheral tolerance mediated by regulatory T (Treg) cells, which represent an obstacle for effective cancer immunotherapy. Although IL-2 is important for effector (E) T cell function, it has been hypothesized that therapies blocking IL-2 signals weaken Treg cell activity, promoting immune responses. This hypothesis has been partially tested using anti-IL-2 or anti-IL-2R Abs with antitumor effects that cannot be exclusively attributed to lack of IL-2 signaling in vivo. In this work, we pursued an alternative strategy to block IL-2 signaling in vivo, taking advantage of the trimeric structure of the IL-2R. We designed an IL-2 mutant that conserves the capacity to bind to the αβ-chains of the IL-2R but not to the γ

Kim G, Hwang H, Jo Y, et al.
Soluble γc receptor attenuates anti-tumor responses of CD8
Int J Cancer. 2018; 143(5):1212-1223 [PubMed] Related Publications
Previous studies have shown that soluble common γ-chain (sγc) modulates CD4

Donskov F, Jensen NV, Smidt-Hansen T, et al.
A randomized phase II trial of interleukin-2 and interferon-α plus bevacizumab versus interleukin-2 and interferon-α in metastatic renal-cell carcinoma (mRCC): results from the Danish Renal Cancer Group (DaRenCa) study-1.
Acta Oncol. 2018; 57(5):589-594 [PubMed] Related Publications
BACKGROUND: Interleukin-2 (IL2)-based immunotherapy is curative for a small subset of patients with metastatic renal-cell carcinoma (mRCC). Preclinical data suggests that bevacizumab (BEV), a humanized anti-VEGF monoclonal antibody, has potential immunomodulatory effects by permitting efficient natural killer (NK) cell-mediated killing and by reverting immune suppression.
PATIENT AND METHODS: We performed a randomized phase II study comparing IL2/IFN (interferon)/BEV with IL2/IFN in favourable/intermediate-risk mRCC patients. One hundred and eighteen patients received IFN 3 MIU subcutaneously (sc) daily and IL2 2.4 MIU/m
RESULTS: Baseline characteristics were well-balanced between the two arms; metastasis-free interval <1 year (75 versus 76%); prior nephrectomy (85 versus 86%); MSKCC favourable/intermediate-risk group (51/49 versus 52%/48%); three or more disease sites (41 versus 44%), respectively. The median PFS was 8.0 mo (95% CI, 4.2-11.9) with IL2/IFN/BEV and 8.1 mo (95% CI, 5.1-11.0) with IL2/IFN, p = .73. There was no difference in secondary endpoints, IL2/IFN/BEV versus IL2/IFN; median time-to-treatment failure (7.4 versus 5.6 mo, p = .54), response rate (44.1 versus 28.8%, p = .13), surgery of residual disease (17.0 versus 17.0%, p = 1.0), patients achieving NED (3.4 versus 8.5%, p = .44), and median overall survival (30.3 versus 34.1 mo, p = .39), respectively. TKI post progression was well-balanced (85 versus 78%). No new/unexpected toxicity was observed. Most common Grade 3/4 adverse events for IL2/IFN/BEV and IL2/IFN were fatigue (64 versus 61%), flu-like symptoms (37 versus 41%) and thrombosis (6.8 versus 18.6%, p = .01), respectively.
CONCLUSIONS: The addition of BEV to IL-2/IFN did not add efficacy in mRCC. (ClinicalTrials.gov, NCT01274273.).

Ceylan K, Jahns LJ, Lode BN, et al.
Inflammatory response and treatment tolerance of long-term infusion of the anti-GD
Pediatr Blood Cancer. 2018; 65(6):e26967 [PubMed] Related Publications
BACKGROUND: The monoclonal anti-GD
METHODS: Fifty-three NB patients received up to six cycles of 100 mg/m
RESULTS: LTI of ch14.18/CHO (d8-18) in combination with s.c.IL-2 (d8-12) showed an acceptable treatment tolerance that allowed all patients to receive part of the treatment as an outpatient (median time point of discharge: d15 for all cycles). The treatment tolerance improved from cycle to cycle and the time to become an outpatient candidate decreased from d15 to d13 in subsequent cycles. Clinical and laboratory parameters indicate a maximum inflammatory response at d11 of each cycle. Interestingly, the soluble IL-2 receptor remained increased at baseline of the next cycle indicating immune activation over the entire treatment period of 6 months.
CONCLUSIONS: LTI of ch14.18/CHO combined with s.c.IL-2 shows an improved tolerance in subsequent cycles allowing outpatient treatment.

Qiao HB, Li J, Lv LJ, et al.
The effects of interleukin 2 and rAd-p53 as a treatment for glioblastoma.
Mol Med Rep. 2018; 17(3):4853-4859 [PubMed] Related Publications
Interleukin 2 (IL-2) is an anti-cancer cytokine that stimulates T cell propagation, triggering innate and adaptive immunity. IL-2 has been used for cancer therapy and has achieved curative effects. Recombinant adenovirus p53 injection (rAd‑p53) is a gene therapeutic agent that may improve the prognosis of patients with glioblastoma (GBM). In the present study, the effect of combined IL‑2 and rAd‑p53 treatment was studied. The ability of IL‑2 to stimulate immunoregulation and the ability of p53 to induce apoptosis for GBM was researched in the GBM tumor model. In addition, the activity of IL‑2 was analyzed. The antitumor potential of IL‑2 and rAd‑p53 was studied using xenograph mice carrying GBM cells. Tumor‑specific CD4+ and CD8+ T cells were also analyzed in the GBM‑bearing models. The results demonstrated that IL‑2 and rAd‑p53 not only stimulated tumor‑specific cytotoxic T‑lymphocyte responses and increased regulatory CD4+ and cytotoxic CD8+ T cell proliferation, however additionally increased expression of apoptosis‑associated genes. The treatment with IL‑2 and rAd‑p53 resulted in tumor regression and prolonged the survival of glioma‑bearing mice. Taken together, a combination of IL‑2 and rAd‑p53 treatment combines the effects of immunotherapy and oncolytic therapy and may be a comprehensive therapeutic schedule for clinical application in future cancer therapies.

Achkar T, Arjunan A, Wang H, et al.
High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features.
PLoS One. 2017; 12(12):e0190084 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: High-dose interleukin-2 (HD IL-2) is used in the treatment of metastatic renal cell carcinoma (mRCC) and has an overall response rate (ORR) of 12-20% and a complete response rate (CR) of 8% in unselected populations with predominantly clear cell type renal cell carcinoma. Nearly 10-15% of patients with renal cell carcinoma exhibit sarcomatoid differentiation, a feature which correlates with a median overall survival (OS) of 9 months and overall poor prognosis. We report a single institution experience with 21 patients with mRCC with sarcomatoid features post-nephrectomy who were treated with HD IL-2.
METHODS: Twenty one patients with mRCC with sarcomatoid features post-nephrectomy who underwent therapy with HD IL-2 were identified at the University of Pittsburgh Medical Center from 2004 to 2016. Baseline patient characteristics, HD IL-2 cycles, time to progression, and subsequent therapies were evaluated. OS and progression-free survival (PFS) in the cohort were calculated using the Kaplan-Meier method. Disease characteristics were evaluated for significance using the Fischer's exact test and Wilcoxon rank sum test.
RESULTS: Patients were predominantly Caucasian males with a median age of 54 years. A majority, 86% of these patients, had metastatic disease at time of initial presentation, primarily with lung and lymph node involvement. The ORR and CR with HD IL-2 was 10% and 5%, respectively. Initial localized disease presentation is the only variable that was significantly associated with response to HD IL-2 (p = 0.0158). Number of HD IL-2 doses did not correlate with response with a mean of 16.5 and 15.0 total doses in responders and non-responders, respectively (p = 0.53). Median PFS with HD IL-2 was 7.9 months (95% CI, 5.0-21.3). Median OS was 30.5 months (95% CI 13.3-57.66). Within the subset of patients who had progression on IL-2, median OS was 19.4 months (95% CI, 13.3-35.3). In patients who received second-line therapy, median PFS was 7.9 months (95% CI 2.4-10.2).
CONCLUSION: In patients with mRCC with sarcomatoid features, use of HD IL-2 was associated with a modest ORR and a higher survival compared to historical controls (patients with mRCC and sarcomatoid features). Thus, HD IL-2 may have a role in treating selected patients with mRCC with sarcomatoid features.

Curti B, Daniels GA, McDermott DF, et al.
Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIM
J Immunother Cancer. 2017; 5(1):102 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIM
METHODS: Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI.
RESULTS: Median follow-up was 3.5+ years (range 1-8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIM
CONCLUSIONS: irAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response.

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