Citations

Introduction/Objective: Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer. Radiation therapy (RT) combined with ICIs and PI3K inhibition may enhance anti-tumor immune activity. Methods: RT-induced cytosolic double-stranded DNA (dsDNA) was measured in human and mouse prostate cancer cell lines as the surrogate upstream marker consistent with cGAS–STING engagement. In a syngeneic mouse model for castration-resistant prostate cancer (Myc-CaP in FVB mice), triple therapies were studied: (1) anti-CTLA-4, anti-PD-1, and RT, and (2) PIM kinase inhibitor PIM447, anti-PD-1, and RT. Mass cytometry (CyTOF) was used to measure the tumor-immune profile. Results: The peak induction of cytosolic dsDNA was at an RT dose of 13 Gy. In the mouse model, triple therapy with anti-CTLA-4, anti-PD-1, and RT doubled the median survival compared to monotherapy (32 days vs 11 to 22 days, p<0.006). Triple therapy with the PIM kinase inhibitor PIM447, anti-PD-1, and RT nearly tripled the median survival compared to PIM447 monotherapy (82 days vs 29 days, p=0.002). Mass cytometry analysis revealed that the combination of anti-PD-1 and RT reduced myeloid-derived suppressor cells and tissue-associated macrophages and enhanced CD8+ T-cell infiltration. Discussion: Although prostate cancer is an immunocold entity, RT can trigger immune activation, consistent with engagement of the cGAS–STING signaling pathway (cytosolic dsDNA serving as a surrogate upstream marker). In triple therapy, RT can enhance the efficacy of ICI and PI3K-targeted drug therapy, significantly improving overall survival in a mouse model of CRPC. Conclusions: A combination of RT, ICIs, and PIM kinase inhibition may help overcome immune resistance in prostate cancer. This combination therapy approach supports further preclinical validation and careful clinical evaluation and warrants further clinical investigation to optimize treatment strategies for CRPC.

EndMT has been reported to contribute to the pathogenesis of PAH. In this study, we aimed to determine the role of Ca 2+ signaling in the development of EndMT in human lung vascular endothelial cells. Our data suggest that TGF-β 1 requires store-operated Ca 2+ entry through STIM1/Orai channels to induce SNAI-mediated EndMT. For the first time, we demonstrated that TGF-β 1 -induced EndMT is a Ca 2+ -dependent event, whereas inhibition of STIM1/Orai interaction attenuated EndMT in response to TGF-β 1 .

Abstract Accumulating evidence suggests that changes in the tumor microenvironment caused by radiotherapy are closely related to the recurrence of glioma. However, the mechanisms by which such radiation‐induced changes are involved in tumor regrowth have not yet been fully investigated. In the present study, how cranial irradiation‐induced senescence in non‐neoplastic brain cells contributes to glioma progression is explored. It is observed that senescent brain cells facilitated tumor regrowth by enhancing the peripheral recruitment of myeloid inflammatory cells in glioblastoma. Further, it is identified that astrocytes are one of the most susceptible senescent populations and that they promoted chemokine secretion in glioma cells via the senescence‐associated secretory phenotype. By using senolytic agents after radiotherapy to eliminate these senescent cells substantially prolonged survival time in preclinical models. The findings suggest the tumor‐promoting role of senescent astrocytes in the irradiated glioma microenvironment and emphasize the translational relevance of senolytic agents for enhancing the efficacy of radiotherapy in gliomas.

Background: Although recently available immune-based approaches in multiple myeloma produce high response rates, curative outcomes have not yet been achieved, which highlights the need for new agents that further activate the immune system without increasing toxicity. ORIC-533 is a highly potent and selective, orally bioavailable, small molecule inhibitor of CD73, an enzyme expressed by various cell types, including immune cells and which catalyzes the generation of adenosine from adenosine monophosphate (AMP) (Allard 2019). Adenosine itself is highly immunosuppressive, diminishing activity of a range of immune cell types, including T, NK, and dendritic cells (Young 2014). By blocking adenosine production from AMP via inhibition of CD73, ORIC-533 has demonstrated the ability to restore and enhance immune function. Multiple myeloma (MM) patient bone marrow (BM) contains multiple cell types that also express CD73, including immune cells, cancer-associated fibroblasts, mesenchymal stem cells, and endothelial cells (Allard 2019). Moreover, elevated adenosine levels in the MM BM niche correlate with disease progression (Horenstein 2016; Yang 2020). We have previously observed that CD73-mediated adenosine activity suppresses the cytolytic antitumor immune function in the MM BM milieu (Ray 2022). ORIC-533 treatment reduced adenosine production, overcame this immune suppression with evidence of restored DC-mediated priming and activated cytotoxic CD8 + T-cell function, and significantly enhanced immune cell cytolytic behavior against RRMM tumor cells in autologous patient ex vivo experiments (Junttila 2022), making ORIC-533 a potential immunotherapy for patients with MM. Methods: ORIC-533-01 (NCT05227144) is an ongoing i3+3 Phase 1b dose escalation study in patients with RRMM. The primary objectives are to determine single agent safety/tolerability and pharmacokinetics (PK) of ORIC-533 to select the RP2D. Pharmacodynamic assessments include measurement of CD73 functional activity in serum and BM, as well as enumeration of immune cell subsets and activation state in blood and BM. Patients are also evaluated for clinical efficacy using IMWG criteria. Results: As of 23 June 2023, 17 patients received ORIC-533 once daily across 4 dose levels (400 mg to 1600 mg). All patients were triple-class refractory, 88% were penta-refractory, and 59% also received prior anti-BCMA/CD3 bispecific therapy or anti-BCMA CAR-T therapy. Overall, ORIC-533 was very well tolerated, with 5 patients experiencing a total of 10 treatment-related adverse events (TRAEs). Fatigue was the only G3 AE and the only TRAE seen in more than 1 patient (1 event each of G3 and G2); all other events seen in 1 patient each, were G1 or G2 in severity, and of no specific system organ class. No dose limiting toxicities, no Grade ≥4 TRAEs, and no treatment-related serious adverse events have been observed. PK showed increased exposure with dose with a plasma half-life of ~24 hrs. Soluble CD73 enzymatic activity was nearly completely inhibited by C1D15 in serum of all patients across all dose levels, while the largest relative suppression in surface CD73 activity in BM cells was observed at the highest dose level. There was also evidence for increases in the abundance of circulating NK and CD8+ T cells after 1 treatment cycle, with preliminary evidence of enhanced CD8+ T-cell activation at the highest dose levels tested in both peripheral blood and BM. In addition, early evidence of single agent clinical activity was observed. Conclusions: ORIC-533 has demonstrated an acceptable safety profile and preliminary evidence of immune activation in a heavily pretreated RRMM patient population. Enrollment is ongoing and updated data will be presented.

Background: Coronary microvascular dysfunction results in angina and adverse outcomes in patients with evidence of ischemia and nonobstructive coronary artery disease; however, no specific therapy exists. CD34+ cell therapy increases microvasculature in preclinical models and improves symptoms, exercise tolerance, and mortality in refractory angina patients with obstructive coronary artery disease. The objective of this research was to evaluate the safety, tolerability, and efficacy of intracoronary CD34+ cell therapy in patients with coronary microvascular dysfunction. Methods: We conducted a 2-center, 20-participant trial of autologous CD34+ cell therapy (protocol CLBS16-P01; NCT03508609) in patients with ischemia and nonobstructive coronary artery disease with persistent angina and coronary flow reserve ≤2.5. Efficacy measures included coronary flow reserve, angina frequency, Canadian Cardiovascular Society angina class, Seattle Angina Questionnaire, SF-36, and modified Bruce exercise treadmill test obtained at baseline and 6 months after treatment. Autologous CD34+ cells (CLBS16) were mobilized by administration of granulocyte-colony stimulating factor 5µg/kg/day for 5 days and collected by leukapheresis. Participants received a single intracoronary left anterior descending infusion of isolated CD34+ cells in medium that enhances cell function. Results: Coronary flow reserve improved from 2.08±0.32 at baseline to 2.68±0.79 at 6 months after treatment ( P <0.005). Angina frequency decreased ( P <0.004), Canadian Cardiovascular Society class improved ( P <0.001), and quality of life improved as assessed by the Seattle Angina Questionnaire ( P ≤0.03, all scales) and SF-36 ( P ≤0.04, all scales). There were no cell-related serious adverse events. Conclusions: In this pilot clinical trial of microvascular angina, patients with ischemia and nonobstructive coronary artery disease receiving intracoronary infusion of CD34+ cell therapy had higher coronary flow reserve, less severe angina, and better quality of life at 6 months. The current study supports a potential therapeutic role for CD34+ cells in patients with microvascular angina. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03508609.

PURPOSE Intrahepatic cholangiocarcinoma (IHCCA), a global health problem, is increasing in incidence and has differing etiologies worldwide. Next-generation sequencing (NGS) is rapidly being incorporated into the clinical management of biliary cancers. IHCCA is enriched with actionable mutations, and there are several promising targeted therapies under development. NGS data from Asia, where IHCCA is most prevalent, are limited. METHODS Comprehensive genomic profiling of formalin-fixed paraffin-embedded tumor tissue from 164 Asian and 283 Western patients with IHCCA was performed using NGS. We measured the distribution of DNA repair genetic aberrations (GAs) in IHCCA, along with actionable mutations. Also, we evaluated the association between DNA repair GAs and tumor mutation burden (TMB). Based on the TMB status, patients were distinguished into 3 levels: low (< 6 mut/Mb), intermediate (6-10 mut/Mb), and high (TMB-H; ≥ 10 mut/Mb). RESULTS Seventy-two percent of Asian patients had ≥ 1 actionable GA, with a significantly higher frequency in KMT2C , BRCA1/2, and DDR2 compared with Western patients ( P = .02, .003, and .003, respectively); 60.9% of Western patients had ≥ 1 actionable GA and higher frequency of CDKN2A/B and IDH1/2 GAs ( P = .0004 and < .001, respectively). GAs in nuclear factor kappa B pathway regulators and DNA repair genes occurred more frequently in Asian patients ( P = .006 and .001, respectively). There was a higher frequency of TMB-H in Asian compared with the Western cohort (12.2% v 5.9%; P = .07). CONCLUSION A higher burden of DNA repair mutations and frequency of patients with TMB-H in the Asian IHCCA cohort compared with the Western patients suggests a potential role for DNA repair and immune checkpoint inhibitors in the Asian population. Future clinical trials should account for this genetic heterogeneity.

Abstract Background: Nilotinib, a 2nd-generation BCR-ABL inhibitor, is 20–30 times more potent than imatinib in vitro. A phase II, open-label study of safety/efficacy of nilotinib in pts with imatinib-resistant/intolerant Ph+ CML-CP or -AP was reported. Planned starting dose was 400mg BID, with escalation to 600mg BID if response was inadequate. The objective of the post-hoc analysis was to evaluate safety/efficacy of nilotinib 600mg BID in CML-CP pts who had dose escalation. Methods: Starting dose was 400mg BID. If response was inadequate (failure to achieve complete hematologic response [CHR] by 3 mos, minimal cytogenetic response [CyR] by 6 mos, or major cytogenetic response [MCyR] by 12 mos; loss of HR, CyR, or progression), nilotinib to 600mg BID dosing was permitted. Imatinib resistance was defined as treatment with imatinib ≥600 mg/d with disease progression (≥50% increase in WBC, blasts, basophils, or platelets) or no HR in peripheral blood and/or bone marrow after 4 wks. Results: Of 320 enrolled pts in CP, 269 remained on nilotinib 400mg BID; 51 pts were dose-escalated to 600mg BID for inadequate responses (mean age 57.7 yrs; 68.6% male). All pts met the study criteria for imatinib resistance. Prior imatinib dose was ≥600mg QD in 98% pts and ≥800 mg QD in 53%. 43/51 (84%) pts had no baseline CHR; 38% had no prior history of complete cytogenetic response (CCyR). 35% had prior MCyR. Median time to dose escalation was 169 (114–211) d. 14 (27.5%) pts remain on therapy; median time to discontinuation from study was 307 (235–414) d. 5 pts with disease progression and no deaths were observed among pts who received 600mg BID. CHR was achieved in 58% of evaluable pts without CHR at baseline (n=43). MCyR occurred in 29% of evaluable pts (15/51) on 600mg BID; 10% (5/51) CCyR. Disease progression was low, occurring in 10% (5/51) of pts on 600mg BID. Median time to progression for CP pts on 600mg BID was 12 mos, substantially less than for pts who stayed on 400mg BID (median not observed yet, at least 20 mo). Nonhematologic AEs in 600mg BID pts were similar to those reported for the entire CP cohort from the phase II study. Grade 3/4 hematologic lab abnormalities were: anemia 13.8%, neutropenia 7.9%, thrombocytopenia 13.7%. Hyperglycemia and elevated bilirubin occurred in 6% and 10% of pts, respectively, on 600mg BID. Conclusions: Some HR and CyR after dose escalation to 600mg BID were observed. Safety/tolerability for 600mg BID were similar to the entire CP cohort. Based on these preliminary data, nilotinib dose escalation to 600mg BID in imatinib-resistant Ph+ CML-CP pts may be effective in pts with inadequate responses to 400mg BID. As might be expected in a more resistant population, response duration was shorter than reported for the phase II CP cohort. Additional follow-up is necessary. Use of 600mg BID is not currently recommended for imatinib-resistant CML-CP pts outside clinical studies.