Cancer Therapeutics
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Item Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial.(ELSEVIER SCI LTD, 2024-07-01) Rescigno, P; Porta, N; Finneran, L; Riisnaes, R; Figueiredo, I; Carreira, S; Flohr, P; Miranda, S; Bertan, C; Ferreira, A; Crespo, M; Rodrigues, DN; Gurel, B; Nobes, J; Crabb, S; Malik, Z; Ralph, C; McGovern, U; Hoskin, P; Jones, RJ; Birtle, A; Gale, J; Sankey, P; Jain, S; McLaren, D; Chadwick, E; Espinasse, A; Hall, E; de Bono, J; Porta, Nuria; Finneran, Laura; Carreira, Suzanne; Crespo, Mateus; Hall, Emma; De Bono, JohannBACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men β₯ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, β₯ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from β₯ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade β₯ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.Item A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations.(NATURE PORTFOLIO, 2024-05-03) Saldana-Guerrero, IM; Montano-Gutierrez, LF; Boswell, K; Hafemeister, C; Poon, E; Shaw, LE; Stavish, D; Lea, RA; Wernig-Zorc, S; Bozsaky, E; Fetahu, IS; Zoescher, P; PΓΆtschger, U; Bernkopf, M; Wenninger-Weinzierl, A; Sturtzel, C; Souilhol, C; Tarelli, S; Shoeb, MR; Bozatzi, P; Rados, M; Guarini, M; Buri, MC; Weninger, W; Putz, EM; Huang, M; Ladenstein, R; Andrews, PW; Barbaric, I; Cresswell, GD; Bryant, HE; Distel, M; Chesler, L; Taschner-Mandl, S; Farlik, M; Tsakiridis, A; Halbritter, F; Poon, Evon; Chesler, LouisEarly childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ female human embryonic stem cell (hESC) differentiation and single-cell transcriptome and epigenome analysis to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNAs impair the specification of trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. This effect is exacerbated upon overexpression of MYCN, whose amplification co-occurs with CNAs in NB. Moreover, CNAs potentiate the pro-tumourigenic effects of MYCN and mutant NC cells resemble NB cells in tumours. These changes correlate with a stepwise aberration of developmental transcription factor networks. Together, our results sketch a mechanistic framework for the CNA-driven initiation of embryonal tumours.Item CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors.(AMER ASSOC CANCER RESEARCH, 2024-04-15) Archer, S; Brailey, PM; Song, M; Bartlett, PD; Figueiredo, I; Gurel, B; Guo, C; Brucklacher-Waldert, V; Thompson, HL; Akinwale, J; Boyle, SE; Rossant, C; Birkett, NR; Pizzey, J; Maginn, M; Legg, J; Williams, R; Johnston, CM; Bland-Ward, P; de Bono, JS; Pierce, AJ; Gurel, Bora; Guo, Wei Yu; De Bono, JohannPURPOSE: CD137 is a T- and NK-cell costimulatory receptor involved in consolidating immunologic responses. The potent CD137 agonist urelumab has shown clinical promise as a cancer immunotherapeutic but development has been hampered by on-target off-tumor toxicities. A CD137 agonist targeted to the prostate-specific membrane antigen (PSMA), frequently and highly expressed on castration-resistant metastatic prostate cancer (mCRPC) tumor cells, could bring effective immunotherapy to this immunologically challenging to address disease. EXPERIMENTAL DESIGN: We designed and manufactured CB307, a novel half-life extended bispecific costimulatory Humabody VH therapeutic to elicit CD137 agonism exclusively in a PSMA-high tumor microenvironment (TME). The functional activity of CB307 was assessed in cell-based assays and in syngeneic mouse antitumor pharmacology studies. Nonclinical toxicology and toxicokinetic properties of CB307 were assessed in a good laboratory practice (GLP) compliant study in cynomolgus macaques. RESULTS: CB307 provides effective CD137 agonism in a PSMA-dependent manner, with antitumor activity both in vitro and in vivo, and additional activity when combined with checkpoint inhibitors. A validated novel PSMA/CD137 IHC assay demonstrated a higher prevalence of CD137-positive cells in the PSMA-expressing human mCRPC TME with respect to primary lesions. CB307 did not show substantial toxicity in nonhuman primates and exhibited a plasma half-life supporting weekly clinical administration. CONCLUSIONS: CB307 is a first-in-class immunotherapeutic that triggers potent PSMA-dependent T-cell activation, thereby alleviating toxicologic concerns against unrestricted CD137 agonism.Item The role of maintenance therapy following autologous stem cell transplantation in newly diagnosed multiple myeloma: Considerations on behalf of the Chronic Malignancies Working Party of the EBMT.(WILEY, 2024-04-01) Hwang, A; Hayden, P; Pawlyn, C; McLornan, D; Garderet, L; Pawlyn, CharlotteRecent treatment advancements in multiple myeloma have led to significant improvements in patient outcomes. Maintenance therapy following autologous haematopoietic stem cell transplantation (AHCT) is now standard of care and has been demonstrated to prolong and deepen treatment responses. Currently, lenalidomide remains the single agent that has been approved for maintenance post-AHCT in Europe and the USA which, if tolerated, is continued until disease progression. The treatment landscape is rapidly expanding however, and the optimal personalised maintenance approach for a patient is becoming more complex. Treatment outcomes for patients with high-risk disease remain poor and choice of maintenance in this population also remains unclear. This review article evaluates up-to-date literature regarding established maintenance approaches. It further analyses ongoing studies exploring maintenance regimens using combination and novel agents, approaches to maintenance in patients with cytogenetic high-risk disease and minimal residual disease response-adapted strategies that reflect the current evolving treatment paradigm.Item CAR T-cell immunotherapy of MET-expressing malignant mesothelioma.(TAYLOR & FRANCIS INC, 2017-12-02) Thayaparan, T; Petrovic, RM; Achkova, DY; Zabinski, T; Davies, DM; Klampatsa, A; Parente-Pereira, AC; Whilding, LM; van der Stegen, SJ; Woodman, N; Sheaff, M; Cochran, JR; Spicer, JF; Maher, J; Klampatsa, AsteroMesothelioma is an incurable cancer for which effective therapies are required. Aberrant MET expression is prevalent in mesothelioma, although targeting using small molecule-based therapeutics has proven disappointing. Chimeric antigen receptors (CARs) couple the HLA-independent binding of a cell surface target to the delivery of a tailored T-cell activating signal. Here, we evaluated the anti-tumor activity of MET re-targeted CAR T-cells against mesothelioma. Using immunohistochemistry, MET was detected in 67% of malignant pleural mesotheliomas, most frequently of epithelioid or biphasic subtype. The presence of MET did not influence patient survival. Candidate MET-specific CARs were engineered in which a CD28+CD3ΞΆ endodomain was fused to one of 3 peptides derived from the N and K1 domains of hepatocyte growth factor (HGF), which represents the minimum MET binding element present in this growth factor. Using an NIH3T3-based artificial antigen-presenting cell system, we found that all 3 candidate CARs demonstrated high specificity for MET. By contrast, these CARs did not mediate T-cell activation upon engagement of other HGF binding partners, namely CD44v6 or heparan sulfate proteoglycans, including Syndecan-1. NK1-targeted CARs demonstrated broadly similar in vitro potency, indicated by destruction of MET-expressing mesothelioma cell lines, accompanied by cytokine release. In vivo anti-tumor activity was demonstrated following intraperitoneal delivery to mice with an established mesothelioma xenograft. Progressive tumor regression occurred without weight loss or other clinical indicators of toxicity. These data confirm the frequent expression of MET in malignant pleural mesothelioma and demonstrate that this can be targeted effectively and safely using a CAR T-cell immunotherapeutic strategy.