The renin-angiotensin-aldosterone system (RAAS), traditionally associated with blood pressure and fluid regulation, also plays a role in tumorigenesis. Renin-angiotensin-aldosterone system inhibitors (RAASI), including angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), have been shown to improve outcomes in various malignant neoplasms. In metastatic urothelial cancer, the use of RAASI have been associated with higher rates of tumor regression in patients receiving immunotherapy (IO) with PD1/L1 inhibitors. This is thought to be due to RAASI-induced downregulation of TGF-beta, for which increased expression is a known mechanism of PD1/L1 inhibitor resistance. We hypothesized that concurrent RAASI in patients with mRCC receiving IO is associated with increased tumor regression.

METHODS:

We conducted a retrospective analysis of patients with mRCC receiving IO as a first- or second-line therapy from 2016-2023 at the University of Virginia. A logistic regression model was used to evaluate the impact of concurrent RAASI on tumor regression. The primary endpoint was any regression of tumor on imaging.

RESULTS:

Data were available for 128 patients with mRCC who received IO as a first- (n = 91, 71.0%) or second- (n = 37, 28.9%) line treatment. Patients who received RAASI during IO were more likely to have tumor regression compared to patients who were not on concurrent RAASI (OR 3.84 [95% CI 1.81-8.47, P =< .001). This held true regardless if patients received IO as a first-line (OR 2.83 [95% CI 1.2-6.94], P = .0173) or second-line (OR 9.5 [95% CI 1.89-73.1], P = .005) treatment.

CONCLUSIONS:

Our hypothesis generating study suggests that in our mRCC population, concurrent use of RAASI in patients receiving IO was associated with a significantly increased likelihood of tumor regression. These findings highlight the potential therapeutic advantage of RAASI in combination with IO for mRCC patients. Further exploration of this association is warranted in prospective studies to improve treatment outcomes for this patient population.

2025-01-01·Drug delivery and translational research

Anti-lung cancer synergy of low-dose doxorubicin and PD-L1 blocker co-delivered via mild photothermia-responsive black phosphorus

Article

作者: Xu, Yong-Hong ; Chen, Xiao ; Chen, Yun ; Li, Tong-Fei ; Han, Ning ; Zhang, Quan ; Chen, Fei-Xiang ; Li, Ke ; Xu, Hua-Zhen

We have previously identified a latent interaction mechanism between non-small cell lung cancer cells (NSCLCC) and their associated macrophages (TAM) mediated by mutual paracrine activation of the HMGB1/RAGE/NF-κB signaling. Activation of this mechanism results in TAM stimulation and PD-L1 upregulation in the NSCLCC. In the present work, we found that free DOX at a low concentration that does not cause DNA damage could activate the HMGB1/RAGE/NF-κB/PD-L1 pathway byinducing oxidative stress. It was thus proposed that a combination of low-dose DOX and a PD-L1 blocker delivered in the NSCLC tumor would achieve synergistic TAM stimulation and thereby synergetic anti-tumor potency. To prove this idea, DOX and BMS-202 (a PD-L1 blocker) were loaded to black phosphorus (BP) nanoparticles after dosage titration to yield the BMS-202/DOX@BP composites that rapidly disintegrated and released drug cargo upon mild photothermal heating at 40 °C. In vitro experiments then demonstrated that low-dose DOX and BMS-202 delivered via BMS-202/DOX@BP under mild photothermia displayed enhanced tumor cell toxicity with a potent synergism only in the presence of TAM. This enhanced synergism was due to an anti-tumor M1-like TAM phenotype that was synergistically induced by low dose DOX plus BMS-202 only in the presence of the tumor cells, indicating the damaged tumor cells to be the cardinal contributor to the M1-like TAM stimulation. In vivo, BMS-202/DOX@BP under mild photothermia exhibited targeted delivery to NSCLC graft tumors in mice and synergistic anti-tumor efficacy of delivered DOX and BMS-202. In conclusion, low-dose DOX in combination with a PD-L1 blocker is an effective strategy to turn TAM against their host tumor cells exploiting the HMGB1/RAGE/NF-κB/PD-L1 pathway. The synergetic actions involved highlight the value of TAM and the significance of modulating tumor cell-TAM cross-talk in tumor therapy. Photothermia-responsive BP provides an efficient platform to translate this strategy into targeted, efficacious tumor therapy.

2024-12-01·JOURNAL OF ONCOLOGY PHARMACY PRACTICE

Successful treatment of PD1-inhibitor induced psoriasiform dermatitis using IL-17 blockade without compromising immunotherapy efficacy

Article

作者: Camou, Monica ; Edmond, Amanda ; Abbott, Jordan ; Penner, Scott ; Niu, Jiaxin ; Greene, Adina

Introduction:

Pembrolizumab is a monoclonal PD-1 inhibitor used in the treatment of lung cancer in addition to several other malignancies. Psoriasiform dermatitis is a well-documented adverse effect.

Case report:

We present a 68 year-old-male with a 50-year smoking history and a 30-year remote history of plaque psoriasis, limited to the knees and elbows, who presented with metastatic non-small cell lung cancer. He was started on a chemotherapy regimen of carboplatin, paclitaxel, and pembrolizumab. One month later, he presented to dermatology with diffuse erythematous scaly papules coalescing into plaques on 80% of body surface area (BSA).

Management & outcome:

Pembrolizumab treatment was paused. The patient was prescribed triamcinolone 0.1% twice daily, but still had significant BSA at one-month and was started on an Il-17 inhibitor, ixekizumab, clearing the psoriasiform dermatitis. He was rechallenged with pembrolizumab every 3 weeks and repeat PET/CT demonstrated excellent tumor response.

Discussion:

This case prompted a literature review to further characterize the use of IL-17 inhibitors for psoriasiform dermatitis in the setting of ICI therapy. All six cases demonstrated improvement of psoriasiform dermatitis, with two cases showing partial response and four cases showing complete resolution. In three of the six cases, the patients exhibited clinical response to the primary malignancy after rechallenging with ICI, while remaining on an IL-17 inhibitor. Our case, in conjunction with the other reported cases, seems to suggest that IL-17 blockade can maintain a fine balance in this challenging clinical scenario by treating psoriasiform dermatitis without compromising the efficacy of immunotherapy.

项与 PD1/PD-L1 Blocker(Crossignal Therapeutics) 相关的新闻（医药）

2023-08-25

·BioSpace

Exelixis Ends Phase III Trial Early Due to ‘Dramatic’ Benefits in Neuroendocrine Tumors

Pictured: Exelixis headquarters/Company courtesy Exelixis on Thursday announced it was unblinding and stopping the pivotal Phase III CABINET trial ahead of schedule, following “dramatic improvement in efficacy” in patients treated with its tyrosine kinase inhibitor Cabometyx (cabozantinib). The decision to stop the trial early is in line with the recommendation of the Independent Data and Safety Monitoring Board of the Alliance for Clinical Trials in Oncology, which found that Cabometyx treatment led to a significantly longer time without disease progression or death in patients with advanced pancreatic and extra-pancreatic neuroendocrine tumors (NET). There is currently no standard of care for patients with these tumors who progress after initial treatment, according to Will Berg, Exelixis’ senior vice president for medical affairs. With its strong performance in CABINET, Cabometyx’s could potentially provide these patients with a new treatment option. The company will discuss the study’s findings with the FDA, Berg said. CABINET is a randomized, double-blinded and placebo-controlled study that enrolled 290 patients, of whom 93 had pancreatic NET and 197 had extra-pancreatic NET. The study’s primary endpoint was progression-free survival (PFS), while key secondary efficacy endpoints included overall survival and radiographic response rate. In terms of safety, CABINET did not detect any new signals of concern and Cabometyx’s adverse event pro consistent with what had been established in prior studies. Cabometyx is a tyrosine kinase inhibitor that works by blocking the MET, AXL and VEGF proteins, all key drivers of tumorigenesis, according to Exelixis’ website. In turn, Cabometyx interferes with crucial cancer functions—such as metastasis and the formation of new blood vessels in the tumor’s environment—while also making cancer cells more sensitive to the immune response. On Monday, this mechanism of action notched Cabometyx a late-stage victory in metastatic castration-resistant prostate cancer when used in combination with Roche’s PD-1/PD-L1 blocker Tecentriq (atezolizumab). In the Phase III CONTACT-02 study, the combination regimen led to a significant improvement in PFS, though only a trend toward better overall survival was reported. Roche and Exelixis are trialing the Tecentriq-Cabometyx combo in several cancer indications and have sustained two Phase III defeats so far: in non-small cell lung cancer in December 2022 and in renal cell carcinoma in March 2023. Cabometyx won its first FDA approval in April 2016 for advanced renal cell carcinoma and it has since picked up indications in hepatocellular carcinoma and thyroid cancer. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

临床3期上市批准临床结果临床终止

2023-08-21

·BioSpace

Roche, Exelixis’ Drug Combo Bounces Back with Late-Stage Prostate Cancer Win

Pictured: Roche Diagnostics headquarters in California/iStock, JHVEPhoto The combination of Roche’s Tecentriq (atezolizumab) and Exelixis’ Cabometyx (cabozantinib) met one of the primary endpoints in the pivotal Phase III CONTACT-02 trial, significantly improving progression-free survival in patients with metastatic castration-resistant prostate cancer, according to interim data released Monday by the companies. In terms of overall survival (OS), however, the combination regimen was only able to elicit a “trend toward improvement” which fell short of statistical significance, the companies reported. CONTACT-02 will continue to its next planned analysis of OS. In terms of safety, the trial found no new signals of concern and the overall adverse event pro consistent with the known side effects of the individual therapies. The companies did not provide specific survival data in its announcement but promised to do so at an upcoming medical conference. Roche and Exelixis, together with international partners Ipsen and Takeda, will also discuss CONTACT-02’s data with the FDA, Exelixis’ Chief Medical Officer Vicki Goodman said in a statement. Despite having been treated with novel hormonal therapies, many metastatic castration-resistant prostate cancer (mCRPC) patients still face poor prognoses of less than two years, Goodman said. Patients whose cancers progress despite treatment need new treatment options, and early results from CONTACT-02 highlight the potential of the Tecentriq-Cabometyx combo to fill this need, she added. Neither Tecentriq nor Cabometyx is approved for prostate cancer. The combination regimen leverages the mechanistic synergy between the two therapies. Cabometyx, a tyrosine kinase inhibitor, works by making a tumor more sensitive to immune responses. Tecentriq is a PD-1/PD-L1 blocker that works by preventing cancer cells from evading the immune system and boosting the body’s natural cytotoxic response. To see this synergistic promise through to the market, Roche and Exelixis signed a clinical trial collaboration agreement in February 2017 and launched a Phase Ib study to target locally advanced or metastatic solid tumors. The partnership, however, has recently yielded mostly disappointing results. In December 2022, the partners suffered a Phase III defeat in non-small cell lung cancer when data from the CONTACT-01 study showed that Tecentriq with Cabometyx could not significantly improve OS in the second-line setting. A few months later, in March 2023, the companies stumbled again—this time in renal cell carcinoma—with data from the CONTACT-03 study showing no significant benefit to progression-free survival after treatment with the combination regimen. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

临床3期临床结果上市批准临床1期抗体药物偶联物

100 项与 PD1/PD-L1 Blocker(Crossignal Therapeutics) 相关的药物交易

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