Citations

Despite advances in treatment, outcomes remain poor for patients with penta-relapsed refractory multiple myeloma (RRMM). In this retrospective analysis, we evaluated the survival outcomes of penta-RRMM patients treated with (BCMA)- directed therapy (BDT). We identified 78 patients with penta-RRMM. Median age was 65 years, 29 (37%) had R-ISS stage III disease, 63 (81%) had high-risk cytogenetics, and 45 (58%) had extra-medullary disease. Median LOT prior to penta-refractory state was 5 (3–12). Amongst penta-RRMM, 43 (55%) were treated with BDT, 35 (45%) were not treated with BDT. Type of BDT received included belantamab mafadotin 15 (35%), Chimeric Antigen Receptor T-cell therapy 9 (21%), BCMA monoclonal antibody 6 (14%), and Bispecific T-cell engager 2 (5%). Eleven (25%) patients received more than one BDT. No significant differences were identified between baseline characteristics for the two groups. Patients treated with a BDT had better median overall survival, 17 vs. 6 months, HR 0.3 p-value < 0.001. Poor performance status, white race, and high-risk cytogenetics were associated with worse outcomes, whereas using a BDT was associated with better outcomes. Patients with penta-refractory MM have poor outcomes. Our retrospective analysis showed a significant survival benefit using BDT when compared to non-BDT for patients with penta-RRMM.

Abstract Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of Aβ42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and Aβ may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.

Abstract Oncolytic virotherapy aims to activate host antitumor immunity, but the effectiveness of current intratumoral herpes-simplex virus (HSV) based monotherapy is limited. Here, to boost the potency of cancer cell targeting α-herpesviruses derived from HSV or Varicella-Zoster Virus (VZV), we coinjected them with myeloid cell-tropic β-herpesviruses derived from cytomegalovirus (CMV) which can powerfully modulate immune responses. Co-administered CMV was shown to promote intratumoral replication of HSV, increase local release of pro-inflammatory cytokines, inhibit adaptive antiviral immune responses, enhance systemic antitumor responses, and lead to superior control of both injected and contralateral tumors. CMV-encoded myeloid-tropic genes, NK evasins (i.e. the vMHC-I homolog), and the m02-m16 region (involved in downregulating classical MHC-I) were implicated in enhancing antitumor activities. CMV is a promising adjuvant to reshape and enhance the antitumor immune responses following α-herpesvirus therapy.

Abstract Oncologic viruses (OV) can induce tumor death through both direct oncolysis and immune-mediated destruction. Our study investigates the use of a novel OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-b) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNb-TYRP1). VSV is an attractive vector since humans are not naturally infected with VSV; thus, pre-existing immunity is minimal. IFN-b leads to increased T-cell responses and tumor cell apoptosis, while TYRP1, a melanocyte differentiation antigen, increases immunogenicity of the therapy. We conducted a Phase 1 clinical trial with a 3+3 design in patients with metastatic uveal melanoma. VSV-IFNb-TYRP1 was injected into a liver metastasis under image guidance, then administered on the same day as a single intravenous (IV) infusion. IV doses started at dose level (DL) 1 1 × 1010 TCID50, then escalated to DL2 3 × 10 10, DL3 1 × 1011, and DL4 3 × 1011. The dose delivered intratumorally (IT) varied based on the IV dose. The primary endpoints were safety and maximum tolerated dose (MTD). Efficacy was a secondary endpoint. Correlative studies focused on understanding viral pharmacokinetics (PK) and immunological responses induced by VSV-IFNb-TYRP1 therapy. Twelve patients with previously treated metastatic uveal melanoma were enrolled. Median follow up was 19.1 months. Four DLs were evaluated with one patient at DL4 experiencing dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). Non-DLTs at DL4 were fatigue, fever, CRS, hematological toxicities (decreased platelets and lymphocytes), and AST elevation. Four patients had stable disease (SD) and 8 had progressive disease (PD) as their best response. ELIspot data show that three of the four patients with response to TYRP1 also had a response to gp100, suggesting possible epitope spreading. These four patients received immune checkpoint inhibitor treatment as the next line of therapy, which led to clinical benefit for two patients. Our study evaluated VSV-IFNb-TYRP1 administered via IT and IV routes in a previously treated population of metastatic uveal melanoma patients and found no major safety events. Although there were no clear objective responses to VSV-IFNb-TYRP1, dose-dependent immunogenicity to melanoma antigens was seen. While OV response alone is not sufficient for clinical benefit, the evidence of epitope spreading is encouraging. Future studies of VSV-IFNb-TYRP1 will evaluate combinations with other therapies. Citation Format: Katherine E. Smith, Adam Weisbrod, Carrie Strand, Jacob Allerd, Jose S. Pulido, Alysha Newsom, Lianwen Zhang, Nandakumar Packiriswamy, Heather Montane, Lisa Kottschade, Anastasios Dimou, Yiyi Yan, Markovic Svetomir, Kah Whye Peng, Richard G. Vile, Matthew S. Block, Roxana S. Dronca. Phase I trial of vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 (VSV-IFNb-TYRP1) in metastatic ocular melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT207.

Abstract Background: Isocitrate dehydrogenase 1/2 (IDH1/2) is mutated in a subset of cholangiocarcinoma (CCA), gliomas, and other solid tumors. LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 study of oral LY3410738 in patients (pts) with IDH1/2m CCA, and IDH1m glioma or other solid tumors. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in advanced IDHm CCA and other solid tumors (NCT04521686). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 80 pts including 42 with CCA (33 IDH1m, 9 IDH2m), 27 with glioma (IDH1m), and 11 other tumor types (IDH1m) received LY3410738 dosed at 25-600 mg QD or 300 mg BID. Pts were median 52 years of age (range, 23-80) with a median of 2 prior therapies (range, 1-7). 19% of CCA pts had received prior IDH1 inhibitor. Median time on treatment was 3.7 months (range, 0.1-19). No DLTs or treatment related deaths were observed; the MTD was not reached. Treatment emergent adverse events (TEAEs) ≥15% included nausea (35%), vomiting (21%), and decreased appetite (19%) and were mostly grade 1-2. Most frequent grade ≥3 TEAEs &gt;2% were anemia (4%), cholangitis (3%), headache (3%), decreased lymphocyte count (3%), and hyponatremia (3%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels, including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Among the 42 pts with R/R CCA, the best response included 1 PR and 22 SD. Of the 22 glioma pts with contrast enhancing tumors, best response included 3 PR and 9 SD. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1/2m advanced solid tumors. Consistent with the expectations for IDH inhibitor monotherapy in this setting, CCA and glioma pts exhibited prolonged stable disease. RP2D evaluation is ongoing. Updated data on LY3410738 monotherapy will be presented at the meeting. Citation Format: Jordi Rodon, Lipika Goyal, Teresa Macarulla Mercade, Masafumi Ikeda, Shunsuke Kondo, Do-Youn Oh, Li-Yuan Bai, Makoto Ueno, Antoine Italiano, Kyriakos Papadopoulos, David Spigel, Sani H. Kizilbash, Rasha Cosman, Joon Oh Park, Li-Tzong Chen, Tomoya Yokota, Anita A. Turk, Chih-Yi Liao, Rachna Shroff, Anthony El-Khoueiry, Taroh Satoh, Antoine Hollebecque, Mitesh J. Borad, Nilofer Azad, Kurt A. Jaeckle, Herbert H. Loong, Jorge Adeva, Wei Peng Yong, Junjie Zhao, Hui Liu, Anna M. Szpurka, Ivelina Gueorguieva, Kamnesh R. Pradhan, Xiaojian Xu, James J. Harding. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced IDH-mutant cholangiocarcinoma and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT098.

Abstract Purpose: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody–drug conjugates (ADC). Experimental Design: TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2–positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2–targeting agents in a mouse xenograft model generated from prostate cancer cell lines. Results: We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti–TROP-2 agents in vivo. Conclusions: These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.

Background Accumulating evidence suggests various specific triggers may lead to new daily persistent headache (NDPH)-like presentations, suggesting that new daily persistent headache is a heterogenous syndrome, and challenging the concept that new daily persistent headache is a primary headache disorder. Method We searched the PubMed database up to August 2022 for keywords including persistent daily headache with both primary and secondary etiologies. We summarized the literature and provided a narrative review of the clinical presentation, diagnostic work-ups, possible pathophysiology, treatment response, and clinical outcomes. Results and conclusion New daily persistent headache is a controversial but clinically important topic. New daily persistent headache is likely not a single entity but a syndrome with different etiologies. The issue with past studies of new daily persistent headache is that patients with different etiologies/subtypes were pooled together. Different studies may investigate distinct subsets of patients, which renders the inter-study comparison, both positive and negative results, difficult. The identification (and removal) of a specific trigger might provide the opportunity for clinical improvement in certain patients, even when the disease has lasted for months or years. Nonetheless, if there is a specific trigger, it remains unknown or unidentified for a great proportion of the patients. We need to continue to study this unique headache population to better understand underlying pathogenesis and, most importantly, to establish effective treatment strategies that hopefully resolve the continuous cycle of pain.

Abstract Background Based on studies from animal models, growth differentiation factor-11 (GDF-11) may have rejuvenating effects in humans. GDF-11 has high sequence homology with GDF-8 (also known as myostatin); follistatin and follistatin-like protein-3 (FSTL-3) are inhibitory proteins of both GDF-8 and GDF-11. Methods Using highly specific liquid chromatography with tandem mass spectrometry assays for GDF-11 and GDF-8 and immunoassays for follistatin and FSTL-3, we quantified the association of these factors with muscle size, strength, and physical performance in 2 prospective cohort studies of community-dwelling older adults (Health, Aging, and Body Composition study [Health ABC] and Cardiovascular Health Study [CHS]). Results GDF-8 levels were positively associated with thigh muscle cross-sectional area and density in Health ABC (data not available in CHS). GDF-8 levels were positively associated with lean mass (a surrogate of muscle mass) in Health ABC but not CHS, and grip strength in CHS but not Health ABC. FSTL-3 (and perhaps follistatin) was negatively associated with lean mass and had variable associations with other variables. In contrast, GDF-11 was not significantly associated with strength or performance. Conclusions GDF-8 and its binding proteins, follistatin and FSTL-3, may constitute a counterregulatory system (chalones) to restrain age-related loss of muscle mass and strength.

Abstract Memory CD8+ T cells protect against secondary viral infections. They develop and maintain exclusively in circulation (e.g. central memory - Tcm) or are excluded from re-circulation (resident memory - Trm). Circulating memory CD8+ T cells arises from memory precursors (MPs) which express memory, pro-survival, and pluripotency molecules. Trm generation, in contrast, is still not fully understood. Previous reports suggest that Trm and Tcm have a common precursor present at the early effector phase; yet, the nature of this precursor is elusive. We have found that the extracellular ATP receptor P2RX7 promotes both Tcm and Trm generation. Moreover, P2RX7 is quickly upregulated in some (but not all) early effectors and early P2RX7 ablation hinders both Tcm and Trm generation. Thus, we postulated that P2RX7 in early effectors may mark a Tcm/Trm common precursor. Comparison between high (P2RX7hi) and low (P2RX7lo) P2RX7-expressing CD8+ T cells shows a correlation between memory markers and P2RX7, with CD62L+ Tcm precursors exclusively found in P2RX7hi cells. RNA-seq of P2RX7hi and P2RX7lo early effectors show survival, memory and pluripotency genes and pathways are upregulated in P2RX7hi cells. Conversely, many terminal effector and apoptosis genes are upregulated in P2RX7lo cells. P2RX7lo early effectors and MPs have increased apoptosis. Upon transfer into infection-matched mice, P2RX7hi MPs preferentially survive and form Tcm compared to P2RX7lo MPs. This is even more apparent when P2RX7hi and P2RX7lo early effectors are compared: approximately 100x more P2RX7hi cells form memory when compared to P2RX7lo cells, both Tcm and Trm. Our data suggest that P2RX7 in early effector CD8+ T cells promotes the generation of a common Tcm/Trm precursor.

Abstract Release of extracellular ATP (eATP) by dying cells is often identified as a "danger signal" by immune cells. However, eATP export by healthy cells is common, and a major transmembrane ATP exporter is the Pannexin 1 (Panx1) molecule. CD8+ T cells express Panx1 during thymic development, at steady-state and during immune response. However, the role of Panx1 on CD8+ T cell-mediated immune response is not well defined. Here, we used genetic and pharmacological ablation tools to address this question. T cell-specific Panx1 deletion does not affect CD8+ T cell thymic development or effector responses to viral infection (LCMV). In contrast, memory CD8+ T cell establishment is impaired by either pharmacological inhibition or CD8-specific Panx1 deletion. Using a tamoxifen-controlled, conditional Panx1 knockout LCMV-specific (P14) CD8+ T cell system, we found that both memory CD8+ T cell generation and survival rely on Panx1. In vitro data further supports these findings: two Panx1 inhibitors, 10Panx and Probenecid, reduce the expression of the central memory marker CD62L. Panx1-deficient CD8+ T cells develop a memory-like phenotype in response to IL-15, but fail to engage mitochondrial respiration and present decreased mitochondrial membrane potential, suggesting Panx1 promotes optimal mitochondrial function. These defects are partially reverted with exogenous eATP. Collectively, our data indicates that cell-intrinsic Panx1-mediated eATP export favors memory CD8+ T cell differentiation. We are currently testing whether CD8-intrinsic Panx1 controls memory CD8+ T cell generation solely as an autocrine eATP source, or if Panx1 also serves as a “rheostat” controlling intracellular ATP levels in antigen-responding CD8+ T cells.