- A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma. [Journal Article]
- OOncoimmunology 2018; 7(5):e1423172
- Background: Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/- MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rational...
Background: Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/- MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. Methods: Patients with unresectable Stage III or IV BRAFV600E mutant melanoma were enrolled in a single-center prospective study (n = 6). Patients were eligible to receive two courses of HD-IL-2 and vemurafenib twice daily. The primary endpoint was progression-free survival (PFS) with secondary objectives including overall survival (OS), response rates (RR), and safety of combination therapy as compared to historical controls. Immune profiling was performed in longitudinal tissue samples, when available. Results: Overall RR was 83.3% (95% CI: 36%-99%) and 66.6% at 12 weeks. All patients eventually progressed, with three progressing on treatment and three progressing after the vemurafenib continuation phase ended. Median PFS was 35.8 weeks (95% CI: 16-57 weeks). Median OS was not reached; however, the time at which 75% of patients were still alive was 104.4 weeks. Change in circulating BRAFV600E levels correlated with response. Though combination therapy was associated with enhanced CD8 T cell infiltrate, an increase in regulatory T cell frequency was seen with HD-IL-2 administration, suggesting a potential limitation in this strategy. Conclusion: Combination vemurafenib and HD-IL-2 is well tolerated and associated with treatment responses. However, the HD-IL-2 induced increase in Tregs may abrogate potential synergy. Given the efficacy of regimens targeting the PD-1 pathway, strategies combining these regimens with BRAF-targeted therapy are currently underway, and the role of combination vemurafenib and HD-IL-2 is uncertain. Trial Registration: Clinical trial information: NCT01754376; https://clinicaltrials.gov/show/NCT01754376.
- Prolonged survival after intraperitoneal interleukin-2 immunotherapy for recurrent ovarian cancer. [Journal Article]
- GOGynecol Oncol Rep 2017; 22:43-44
- •A case report of a 14 year remission of recurrent ovarian cancer with intraperitoneal aldesleukin (IL-2) is presented.•Intraperitoneal IL-2 was given with little toxicity.•Immunotherapy may have the...
•A case report of a 14 year remission of recurrent ovarian cancer with intraperitoneal aldesleukin (IL-2) is presented.•Intraperitoneal IL-2 was given with little toxicity.•Immunotherapy may have the potential for durable remissions in ovarian cancer.
- Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial. [Journal Article]
- WOWellcome Open Res 2017; 2:28
- CONCLUSIONS: The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection.
- Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines. [Journal Article]
- OOncoimmunology 2017; 6(3):e1277306
- We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C...
We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the therapeutic index of IL-2 therapy by (a) preferential retention at the tumor by having a lower dissociation rate from CEA-expressing cancer cells vs. IL-2R-expressing cells, (b) avoiding any FcγR-binding and Fc effector functions and (c) reduced binding to endothelial cells expressing CD25; and (iii) improve the pharmacokinetics, and thus convenience of administration, of IL-2. The crystal structure of the IL2v-IL-2Rβγ complex was determined and CEA-IL2v activity was assessed using human immune effector cells. Tumor targeting was investigated in tumor-bearing mice using (89)Zr-labeled CEA-IL2v. Efficacy studies were performed in (a) syngeneic mouse models as monotherapy and combined with anti-PD-L1, and in (b) xenograft mouse models in combination with ADCC-mediating antibodies. CEA-IL2v binds to CEA with pM avidity but not to CD25, and consequently did not preferentially activate Tregs. In vivo, CEA-IL2v demonstrated superior pharmacokinetics and tumor targeting compared with a wild-type IL-2-based CEA immunocytokine (CEA-IL2wt). CEA-IL2v strongly expanded NK and CD8(+) T cells, skewing the CD8(+):CD4(+) ratio toward CD8(+) T cells both in the periphery and in the tumor, and mediated single agent efficacy in syngeneic MC38-CEA and PancO2-CEA models. Combination with trastuzumab, cetuximab and imgatuzumab, all of human IgG1 isotype, resulted in superior efficacy compared with the monotherapies alone. Combined with anti-PD-L1, CEA-IL2v mediated superior efficacy over the respective monotherapies, and over the combination with an untargeted control immunocytokine. These preclinical data support the ongoing clinical investigation of the cergutuzumab amunaleukin immunocytokine with abolished CD25 binding for the treatment of CEA-positive solid tumors in combination with PD-L1 checkpoint blockade and ADCC competent antibodies.
- Low-dose interleukin-2 promotes STAT-5 phosphorylation, Tregsurvival and CTLA-4-dependent function in autoimmune liver diseases. [Journal Article]
- CEClin Exp Immunol 2017; 188(3):394-411
- CD4+CD25highCD127lowforkhead box protein 3 (FoxP3+) regulatory T cells (Treg) are essential for the maintenance of peripheral tolerance. Impaired Tregfunction and an imbalance between effector and Tr...
CD4+CD25highCD127lowforkhead box protein 3 (FoxP3+) regulatory T cells (Treg) are essential for the maintenance of peripheral tolerance. Impaired Tregfunction and an imbalance between effector and Tregscontribute to the pathogenesis of autoimmune diseases. We reported recently that the hepatic microenvironment is deficient in interleukin (IL)-2, a cytokine essential for Tregsurvival and function. Consequently, few liver-infiltrating Tregdemonstrate signal transducer and activator of transcription-5 (STAT-5) phosphorylation. To establish the potential of IL-2 to enhance Tregtherapy, we investigated the effects of very low dose Proleukin (VLDP) on the phosphorylation of STAT-5 and the subsequent survival and function of Tregand T effector cells from the blood and livers of patients with autoimmune liver diseases. VLDP, at less than 5 IU/ml, resulted in selective phosphorylation of STAT-5 in Tregbut not effector T cells or natural killer cells and associated with increased expression of cytotoxic T lymphocyte antigen-4 (CTLA-4), FoxP3 and CD25 and the anti-apoptotic protein Bcl-2 in Tregwith the greatest enhancement of regulatory phenotype in the effector memory Tregpopulation. VLDP also maintained expression of the liver-homing chemokine receptor CXCR3. VLDP enhanced Tregfunction in a CTLA-4-dependent manner. These findings open new avenues for future VLDP cytokine therapy alone or in combination with clinical grade Tregin autoimmune liver diseases, as VLDP could not only enhance regulatory phenotype and functional property but also the survival of intrahepatic Treg.
- Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIM(SM). [Journal Article]
- CGClin Genitourin Cancer 2017; 15(1):31-41.e4
- CONCLUSIONS: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients.
- FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma. [Clinical Trial]
- CCClin Cancer Res 2017 May 01; 23(9):2159-2168
- Purpose: Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated antitumor responses when tumor-reactive antibodie...
Purpose: Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated antitumor responses when tumor-reactive antibodies are present. The affinity of the FCGR/antibody interaction is variable and dependent uponFCGRpolymorphisms. Prior studies of patients with cancer treated with immunotherapy indicate thatFCGRpolymorphisms can influence antitumor response for certain immunotherapies that act via therapeutically administered mAbs or via endogenous tumor-reactive antibodies induced from tumor antigen vaccines. The previously published "SELECT" trial of high-dose aldesleukin (HD-IL2) for metastatic renal cell carcinoma resulted in an objective response rate of 25%. We evaluated the patients in this SELECT trial to determine whether higher-affinityFCGRpolymorphisms are associated with outcome.Experimental Design:SNPs inFCGR2A, FCGR3A, andFCGR2Cwere analyzed, individually and in combination, for associations between genotype and clinical outcome.Results:When higher-affinity genotypes forFCGR2A, FCGR3A, andFCGR2Cwere considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2.Conclusions:Although associations of higher-affinityFCGRgenotype with clinical outcome have been demonstrated with mAb therapy and with idiotype vaccines, to our knowledge, this is the first study to show associations ofFCGRgenotypes with outcome following HD-IL2 treatment. We hypothesize that endogenous antitumor antibodies may engage immune cells through their FCGRs, and HD-IL2 may enhance antibody-induced tumor destruction, or antibody-enhanced tumor antigen presentation, via augmented activation of innate or adaptive immune responses; this FCGR-mediated immune activity would be augmented through immunologically favorable FCGRs.Clin Cancer Res; 23(9); 2159-68. ©2016 AACR.
- Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial. [Randomized Controlled Trial]
- PMPLoS Med 2016; 13(10):e1002139
- CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D.
- A novel therapeutic paradigm for patients with extensive alopecia areata. [Review]
- EOExpert Opin Biol Ther 2016; 16(8):1005-14
- CONCLUSIONS: The translational revolution leading to improved therapeutic strategies has just begun for AA. These treatments are often associated with better safety and higher efficacy compared to currently used immune-suppressants. Different pathways might drive the inflammatory process in AA. Ongoing and future clinical trials utilizing narrow- targeted therapeutics will be able to better elucidate the role of each cytokine pathway in creating the AA disease phenotype.
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- Interleukin-2 Therapy Induces CD4 Downregulation, Which Decreases Circulating CD4 T Cell Counts, in African Green Monkeys. [Journal Article]
- JVJ Virol 2016 Jun 15; 90(12):5750-8
- African green monkeys (AGMs) are natural hosts of simian immunodeficiency virus (SIVAGM). Because these animals do not develop simian AIDS despite maintaining high viral loads, there is considerable ...
African green monkeys (AGMs) are natural hosts of simian immunodeficiency virus (SIVAGM). Because these animals do not develop simian AIDS despite maintaining high viral loads, there is considerable interest in determining how these animals have evolved to avoid SIV disease progression. Unlike nonnatural hosts of SIV, adult AGMs maintain low levels of CD4(+) T cells at steady states and also have a large population of virus-resistant CD8αα T cells that lack CD4 expression despite maintaining T helper cell functionalities. In recent work, we have shown that homeostatic cytokines can induce CD4 downregulation in AGM T cells in vitro Through administering therapeutic doses of recombinant human interleukin-2 (IL-2) to AGMs, we show here that this mechanism is operative in vivo IL-2 therapy induced transient yet robust proliferation in all major T cell subsets. Within the CD4(+) T cell population, those that were induced into cycle by IL-2 exhibited characteristics of CD4-to-CD8αα conversion. In all animals receiving IL-2, circulating CD4(+) T cell counts and proportions tended to be lower and CD4(-) CD8αα(+) T cell counts tended to be higher. Despite reductions in circulating target cells, the viral load was unaffected over the course of study.