0
selected
-
1.
Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma: Final results of cohorts A, G, H and I of IVY Phase I study.
Tannir, NM, Papadopoulos, KP, Wong, DJ, Aljumaily, R, Hung, A, Afable, M, Kim, JS, Ferry, D, Drakaki, A, Bendell, J, et al
International journal of cancer. 2021;(2):403-408
-
-
Free full text
-
Abstract
Interleukin (IL)-10 has anti-inflammatory and CD8+ T-cell-stimulating properties. Pegilodecakin (pegylated recombinant human IL-10) induces intratumoral antigen-specific CD8 + T-cells and upregulates IFNγ and major histocompatibility complexes (MHC) I and II. Pegilodecakin has single-agent activity with manageable toxicity in advanced renal cell carcinama (aRCC) (data cutoff 24 March 2016). Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long-term follow-up with pegilodecakin + anti-programmed cell death 1 (anti-PD-1) inhibitors (data cutoff 19 February 2019). Phase 1/1b multi-cohort dose escalation IVY study enrolled 353 patients. Sixty-six patients with aRCC were treated with pegilodecakin alone or with pazopanib or anti-PD-1 inhibitor in cohorts A, G, H and I (data cutoff 19 February 2019). Primary endpoints included safety and tolerability. Secondary endpoint was tumor response by immune-related response criteria (irRC). Pegilodecakin plus nivolumab or pembrolizumab yielded median progression-free survival (mPFS) of 13.9 months and 6-month PFS probability of 60%, 76% 1-year overall survival (OS) probability and 61% 2-year OS probability. Pegilodecakin monotherapy produced mPFS of 1.8 months, 6-month PFS probability 25%, 1-year OS 50%, and 2-year OS 17%. Median OS was not reached in both combinations. Objective response rates (ORRs) were 33% with pazopanib and 43% with anti-PD-1. Most common Grade 3/4 treatment-related adverse events included anemia, thrombocytopenia and hypertriglyceridemia. In these heavily pretreated renal cell carcinama cohorts of IVY, pegilodecakin+anti-PD-1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti-PD-1 inhibitors was consistent as previously reported.
-
2.
Renal Toxicity of Systemic Therapy for Renal Cell Carcinoma.
Jaimes, EA
Seminars in nephrology. 2020;(1):49-58
Abstract
The incidence of kidney cancer has been increasing steadily and, until recently, there was a substantial lack of effective therapies for a cancer that is now among the 10 most common cancers in men and women. During the past 10 years, novel therapies have been developed including antiangiogenic drugs targeting vascular endothelial growth factor and its receptors, immune checkpoint inhibitors, and mammalian target of rapamycin inhibitors that have resulted in a significant improvement in clinical outcomes in a traditionally difficult-to-treat cancer. These new drugs, however, also have important side effects and toxicities that often have an impact on the treatment of these patients. The use of anti-angiogenic drugs often results in the development of hypertension and, less frequently, varying degrees of proteinuria including nephrotic range proteinuria. A variety of agents are used for the treatment of hypertension and proteinuria including blockers of the renin angiotensin system and calcium channel blockers, but there are no randomized clinical trials comparing different therapeutic agents in these patients. Immune checkpoint inhibitors have become one of the cornerstones of therapy in kidney cancer, but their use is linked to a variety of side effects that affect almost every organ and resemble autoimmune diseases. In the kidney, these drugs can induce acute interstitial nephritis in close to 5% of patients with varying degrees of severity that in some cases require discontinuation of treatment and systemic treatment with corticosteroids. Although mammalian target of rapamycin inhibitors now also are part of the therapeutic armamentarium available for these patients, all clinical trials have been performed in patients with normal renal function and therefore their effects in patients with abnormal renal function are not known.
-
3.
Primary hypothyroidism and isolated ACTH deficiency induced by nivolumab therapy: Case report and review.
Zeng, MF, Chen, LL, Ye, HY, Gong, W, Zhou, LN, Li, YM, Zhao, XL
Medicine. 2017;(44):e8426
-
-
Free full text
-
Abstract
RATIONALE Nivolumab is a monoclonal IgG antibody blocking programmed death receptor-1 (PD1), leading to restoration of the natural T-cell-mediated immune response against the cancer cells. However, it also causes plenty of autoimmune-related adverse events, which often involves endocrine system. PATIENT CONCERNS A 54-year-old male with renal clear cell carcinoma was treated with nivolumab intravenously. Routine monitoring showed elevated thyroid-stimulating hormone and low free thyroxine after the 6th administration of nivolumab. After the 12th administration, he developed general fatigue, recurrent hypoglycemia, and relative hypotension. Laboratory tests showed low sodium, low morning cortisol without correspondence increase of corticotrophin (ACTH). Other pituitary hormones were normal. MRI showed no space-occupying lesions, but heterogeneous enhancement of the pituitary gland. DIAGNOSES Primary hypothyroidism and isolated ACTH deficiency. The etiologies were assumed to be nivolumab induced autoimmune lymphocytic thyroiditis and hypophysitis, respectively. INTERVENTIONS Hormone replacements with levothyroxine and acetate cortisone were given orally. Nivolumab was adjusted to lower dose and longer interval. OUTCOMES The patient felt good after adequate replacement. Nivolumab was returned to routine dose and interval six months later. And the metastasis was not obviously progressed during this time. LESSONS The present report provides the first detailed presentation of combined hypothyroidism and isolated ACTH deficiency induced by nivolumab. Adrenal deficiency often develops insidiously. We suggest routine monitoring of fasting blood-glucose, blood pressure and serum sodium as well as thyroid function during nivolumab and other cancer immunotherapies. When unexpected fatigue, hypoglycemia, hypotension or hyponatremia appeared, adrenal deficiency should be taken into consideration.
-
4.
The Therapeutic Aspects of the Endocannabinoid System (ECS) for Cancer and their Development: From Nature to Laboratory.
Khan, MI, Sobocińska, AA, Czarnecka, AM, Król, M, Botta, B, Szczylik, C
Current pharmaceutical design. 2016;(12):1756-66
-
-
Free full text
-
Abstract
The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids' mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field.
-
5.
Identification of an immunogenic CTL epitope of HIFPH3 for immunotherapy of renal cell carcinoma.
Sato, E, Torigoe, T, Hirohashi, Y, Kitamura, H, Tanaka, T, Honma, I, Asanuma, H, Harada, K, Takasu, H, Masumori, N, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2008;(21):6916-23
Abstract
PURPOSE CD8(+) CTLs have an essential role in immune response against tumor. Although tumor-associated antigens have been identified in renal cell carcinoma (RCC), few of these are commonly shared and investigated as therapeutic targets in the clinical medicine. In this report, we show that HIFPH3, a member of prolyl hydroxylases that function as oxygen sensor, is a novel tumor antigen and HIFPH3-specific CTLs are induced from peripheral blood lymphocytes of RCC patients. EXPERIMENTAL DESIGN Expression of HIFPH3 was examined by reverse transcription-PCR and immunostaining with anti-HIFPH3 antibody. To identify HLA-A24-restricted T-cell epitopes of HIFPH3, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. Peptide-specific CTLs were induced by stimulating peripheral blood lymphocytes of HLA-A24-positive RCC patients with these peptides in vitro. HLA-A24-restricted cytotoxicity of the CTLs against HIFPH3(+) RCC lines was assessed by chromium release assay. RESULTS HIFPH3 was overexpressed in many RCC cell lines and primary RCC tissues, whereas it was not detectable in normal adult tissues by reverse transcription-PCR. Of the eight peptides that contained HLA-A24-binding motif, HIFPH3-8 peptide (amino acid sequence, RYAMTVWYF) could induce the peptide-specific CTLs from 3 of 6 patients with HIFPH3-positive RCC. Furthermore, HIFPH3-8 peptide-specific CTLs showed cytotoxicity against HIFPH3(+) RCC cell lines in a HLA-A24-restricted manner. CONCLUSIONS HIFPH3 may be a target antigen in immunotherapy for RCC and HIFPH3-8 peptide could be used as a peptide vaccine for HLA-A*2402(+)/HIFPH3(+) RCC patients.
-
6.
Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma.
Kusmartsev, S, Su, Z, Heiser, A, Dannull, J, Eruslanov, E, Kübler, H, Yancey, D, Dahm, P, Vieweg, J
Clinical cancer research : an official journal of the American Association for Cancer Research. 2008;(24):8270-8
Abstract
PURPOSE Tumor-induced immunosuppression remains a significant obstacle that limits the efficacy of biological therapy for renal cell carcinoma. Here we evaluate the role of CD33 myeloid-derived suppressor cells (MDSC) in the regulation of T-cell responses in renal cell carcinoma patients. We also examine effect of all-trans-retinoic acid (ATRA) on MDSC-mediated immune suppression. EXPERIMENTAL DESIGN CD33-positive myeloid cells were isolated from the peripheral blood of renal cell carcinoma patients with magnetic beads and tested in vitro for their ability to inhibit T-cell responses. T-cell function was evaluated using ELISPOT and CTL assays. RESULTS MDSC isolated from renal cell carcinoma patients, but not from healthy donors, were capable of suppressing antigen-specific T-cell responses in vitro through the secretion of reactive oxygen species and nitric oxide upon interaction with CTL. MDSC-mediated immune suppression and IFN-gamma down-regulation was reversible in vitro by exposing cells to the reactive oxygen species inhibitors. Moreover, ATRA was capable of abrogating MDSC-mediated immunosuppression and improving T-cell function by direct differentiation into antigen-presenting cell precursors. CONCLUSIONS These results may have significant implications regarding the future design of active immunotherapy protocols that may include differentiation agents as part of a multimodal approach to renal cell carcinoma immunotherapy.
-
7.
Obesity, interrelated mechanisms, and exposures and kidney cancer.
Moyad, MA
Seminars in urologic oncology. 2001;(4):270-9
Abstract
Obesity has been shown to increase the risk or be associated with numerous conditions from cardiovascular disease and type II diabetes to erectile dysfunction and osteoarthritis. Obesity may also be associated with numerous cancers, and kidney cancer or renal-cell cancer (RCC) may have one of the strongest correlations to obesity compared with cancer at any other site. Almost every epidemiologic investigation has demonstrated an association that tends to affect women more than men, but both genders are impacted. In general, past studies suggest that with increasing weight, a threshold point exists whereby a certain range of body mass index dramatically changes risk. Men and women at the most extreme ends of obesity tend to have the highest risk or only risk in past studies. Individuals at the more extreme ends of obesity may be affected by an almost indefinite number of mechanisms and exposures that could determine incidence and possibly prognosis. For example, higher estrogen levels, elevated insulin levels, a greater concentration of growth factors in adipose tissue, hypertension, cholesterol metabolism abnormalities, and immune malfunction are just some of the potential mechanisms that may increase kidney cancer risk. Obese individuals may also have lower serum levels of vitamin D and engage in less physical activity. Smoking or genetic predisposition to RCC may synergistically contribute to the effect of obesity on risk. The potential mechanisms and associations are numerous and complex. Regardless of the actual cancer risk now and in the future, the overall effect of obesity on general health is clear, and this should be kept in mind in the discussion between health professional and patient.