Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors.

PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

An update on the status of HSP90 inhibitors in cancer clinical trials.

The evolutionary conserved molecular chaperone heat shock protein 90 (HSP90) plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins (HSPs) involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors (HSP90i) have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov. Among these trials, 60 % have been completed, 10 % are currently active, and 30 % have been suspended, terminated, or withdrawn. HSP90 inhibitors (HSP90i) have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90i are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90i have shown limited clinical activity due to drug-related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune checkpoint inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests the potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past 5 years regarding HSP90i and their implications in anticancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90i as promising therapeutic agents in cancer treatment.

Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers.

Background: LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies. Methods: A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLN-expressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets. Results: The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed. Discussion: Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. Clinical trial registration: https://www.clinicaltrials.gov/study/NCT04034238.

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma.

BACKGROUND: ONC201 is a small molecule that can cause nonapoptotic cell death through loss of mitochondrial function. Results from the phase I/II trials of ONC201 in patients with refractory solid tumors demonstrated tumor responses and prolonged stable disease in some patients. METHODS: This single-arm, open-label, phase II clinical trial evaluated the efficacy of ONC201 at the recommended phase II dose (RP2D) in patients with recurrent or refractory metastatic breast or endometrial cancer. Fresh tissue biopsies and blood were collected at baseline and at cycle 2 day 2 for correlative studies. RESULTS: Twenty-two patients were enrolled; 10 patients with endometrial cancer, 7 patients with hormone receptor-positive breast cancer, and 5 patients with triple-negative breast cancer. The overall response rate was 0%, and the clinical benefit rate, defined by complete response (CR) + partial response (PR) + stable disease (SD), was 27% (n = 3/11). All patients experienced an adverse event (AE), which was primarily low grade. Grade 3 AEs occurred in 4 patients; no grade 4 AEs occurred. Tumor biopsies did not show that ONC201 consistently induced mitochondrial damage or alterations in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the TRAIL death receptors. ONC201 treatment caused alterations in peripheral immune cell subsets. CONCLUSION: ONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027).

Seasonal plasticity in immunocompetent cytokines (IL-2, IL-6, and TNF-α), myeloid progenitor cell (CFU-GM) proliferation, and LPS-induced oxido-inflammatory aberrations in a tropical rodent Funambulus pennanti: role of melatonin.

In seasonal breeders, photoperiods regulate the levels of circulatory melatonin, a well-known immunomodulator and an antioxidant. Melatonin is known to play a complex physiological role in maintaining the immune homeostasis by affecting cytokine production in immunocompetent cells. In this study, we have quantified seasonal and temporal variations in immunocompetent cytokines-IL-2, IL-6, and TNF-α-and circulatory corticosterone along with in- vitro proliferation of bone marrow-derived granulocyte macrophage-colony forming unit (CFU-GM) progenitor cells of a tropical seasonal breeder Funambulus pennanti (northern palm squirrel). Transient variations in antioxidant status of seasonal breeders might be due to the fluctuations associated with immunity and inflammation. Further, to establish a direct immunomodulatory effect of photoperiod, we recorded the LPS-induced oxidative and inflammatory responses of squirrels by housing them in artificial photoperiodic chambers mimicking summer and winter seasons respectively. We observed a marked variation in cytokines level, melatonin, and corticosterone , and CFU-GM cell proliferation during summer and winter seasons. High Peripheral melatonin levels directly correlated with cytokine IL-2 levels, and inversely correlated with TNF-α, and circulatory corticosterone level. LPS-challenged squirrels housed in short photoperiod (10L:14D; equivalent to winter days) showed a marked reduction in the components of the inflammatory cascade, CRP, TNF-α, IL-6, NOx, NF-κB, Cox-2, and PGES, with an overall improvement in antioxidant status when compared to squirrels maintained under a long photoperiod (16L:8D; equivalent to summer days). Our results underline the impact of seasonality, photoperiod, and melatonin in maintaining an intrinsic redox-immune homeostasis which helps the animal to withstand environmental stresses.

Role of melatonin and HSF-1\HSP-70 in modulating cold stress-induced immunosuppression in a tropical rodent- Funambulus pennanti [Volume 87, January 2020, 102456].

The neuroendocrine hormone melatonin and molecular chaperones (heat shock proteins) are evolutionarily conserved molecules that play an important role in protecting organisms from abiotic and biotic stressors. Environmental temperature and seasonality modulates immunity which impacts the overall health of animals. Most studies in relation to thermal stress are based on animals inhabiting temperate zones however, the substantial effect of climatic stress on tropical animals is less explored. Therefore, in this study we focused on the immunosuppressive effect of cold environment on a seasonally breeding tropical rodent and highlighted the importance of melatonin and HSF-1/Hsp-70 in regulating immunity. Animals were exposed to different temperatures with or without melatonin treatment. Our results suggest that, low temperature elicited cold-associated stress in animals marked by reduced body weight, decreased TLC/LC count in the blood and increased corticosterone production which was central to all immune alterations. Cold temperature also increased the oxidative stress which further induced apoptosis in the immune cells and activated stress response molecular chaperones HSF-1/HSP-70. Exogenous melatonin treatment not only ameliorated cold-induced immune suppression but also upregulated the expression of HSF-1 and HSP-70 in the immune cells thereby preventing protein unfolding and cell death. Thus, we conclude that melatonin and molecular chaperones synergistically alleviated immune suppression and could emerge as a promising combination therapy to target temperature stress in animals while boosting immunity.

Comparative effect of melatonin and quercetin in counteracting LPS induced oxidative stress in bone marrow mononuclear cells and spleen of Funambulus pennanti.

A majority of cellular diseases, independent of their origin, are characterized by a dramatic increase in Reactive Oxygen Species (ROS) in response to stress. In most cases, the uncontrolled detrimental ROS outburst is difficult to handle for the cellular machinery and eventually leads to cell mortality. In this study, we compare the antioxidant efficacy of quercetin and melatonin to find out a better alternative against lipopolysaccharide (LPS) induced tissue injury by oxidative stress in Funambulus pennanti. Transient exposure to LPS significantly increased ROS generation and lipid peroxidation levels in bone marrow mononuclear cells (MNCs) and spleen which was further corroborated by decreased activities of SOD, CAT and Gpx enzymes. It also downregulate the expression of cellular oxidative stress response proteins Nrf-2 and HO-1 in spleen and decreases the proliferation of bone marrow derived Granulocyte macrophage-colony forming unit cells (GM-CFU). Both melatonin and quercetin pre-treatments rescued these effects, however, our results indicated that the efficacy of melatonin to overcome oxidative stress was significantly better than quercetin. Our findings support the idea that melatonin is a better antioxidant and immunomodulator as compared to other alternatives and perhaps may be employed in the development of effective therapeutics against ROS dominated diseases.