Recurrent or Refractory High-Grade Gliomas Treated by Convection-Enhanced Delivery of a TGFβ 2-Targeting RNA Therapeutic: A Post-Hoc Analysis with Long-Term Follow-Up

Fatih M Uckun, Sanjive Qazi, Larn Hwang, Vuong N Trieu, Fatih M Uckun, Sanjive Qazi, Larn Hwang, Vuong N Trieu

Abstract

Background. OT101 is a first-in-class RNA therapeutic designed to abrogate the immunosuppressive actions of transforming growth factor beta 2 (TGFβ2). Here, we report our post-hoc analysis of the single-agent activity of OT101 in adult patients with recurrent and/or refractory (R/R) high-grade gliomas. Methods. In a Phase 2 clinical trial (ClinicalTrials.gov, NCT00431561), OT101 was administered to 89 R/R high-grade glioma (HGG) (anaplastic astrocytoma/AA: 27; glioblastoma multiforme/GBM: 62) patients with an intratumoral catheter using a convection enhanced delivery (CED) system. Seventy-seven patients (efficacy population; GBM: 51; AA: 26) received at least the intended minimum number of four OT101 treatment cycles. Response determinations were based on central review of magnetic resonance imaging (MRI) scans according to the McDonald criteria. Standard statistical methods were applied for the analysis of data. Findings. Nineteen patients had a complete response (CR) or partial response (PR) following a slow but robust size reduction of their target lesions (median time for 90% reduction of the baseline tumor volume = 11.7 months, range: 4.9-57.7 months). The mean log reduction of the tumor volume was 2.2 ± 0.4 (median = 1.4: range: 0.4-4.5) logs. In addition, seven patients had a stable disease (SD) lasting ≥6 months. For the combined group of 26 AA/GBM patients with favorable responses, the median progression-free survival (PFS) of 1109 days and overall survival (OS) of 1280 days were significantly better than the median PFS (p < 0.00001) and OS (p < 0.00001) of the non-responders among the 89 patients or the 77-patient efficacy population. Conclusion. Intratumorally administered OT101 exhibits clinically meaningful single-agent activity and induces durable CR/PR/SD in R/R HGG patients.

Keywords: RNA therapeutic; glioma; immuno-oncology.

Conflict of interest statement

F.M.U., V.N.T., and L.H. are employees and shareholders of Oncotelic, the sponsor for clinical development of OT101. V.N.T. and L.H. are listed as inventors on patents and patent applications related to OT101. S.Q. received compensation from Oncotelic as a consultant.

Figures

Figure 1
Figure 1
(A) Waterfall plot of Maximum Tumor Reductions of the 26-patient Favorable Response Population: A waterfall plot is depicted to show the maximum tumor reduction relative to baseline (% reduction of the 3-D volume of the target lesion) in each of the 19 recurrent and/or refractory (R/R) high grade glioma patients who had a complete response (CR), partial response (PR) or stable disease lasting ≥6 months to OT101 single agent therapy. Vertical bars on these plots measured maximum reduction in tumor volumes of the treated target lesions following OT101 treatment. The best overall response (BOR) for each patient are indicated with specific symbols. (B) Swimmer Plot of Best Overall Responses of the 26-patient Favorable Response Population: The onset and duration of CR/PR, end of the objective response (OR) and onset of progression of disease (PD) are indicated with specific symbols. In patient 404705, the PD was an unconfirmed single point determination based on a follow-up MRI. In patient 3100510, the BOR determination was based on local review of the MRI data; the BOR was based on central review of MRI scans in others. See Table S9 for additional details.
Figure 2
Figure 2
MRI-response of target lesion in OT101 treated R/R high-grade glioma patients. Depicted are T1-weighted spin echo (SE) post-contrast axial MRI images at baseline vs. post-treatment with OT101 at 433 days post randomization to their respective OT101 dose cohorts. Panels A and B: Unique patient number (UPN) 405-0704 (anaplastic astrocytoma (AA), WHO Grade III) achieved a CR. Panels C and D: UPN4050412 (glioblastoma multiforme (GBM), WHO Grade IV) achieved a PR.
Figure 3
Figure 3
Swimmer plot for onset and duration of intratumoral edema and/or pseudoprogression for 14 patients with CR or PR as their BOR. The onset and end of intratumor edema, pseudo-progression and onset of PD are indicated with specific symbols. In patient 404705, the PD was an unconfirmed single point determination based on day 1422 follow-up MRI.
Figure 4
Figure 4
Pseudo-progression and CR in R/R AA (WHO Grade 3) patient, UPN203302. (A–D): Depicted are T1-weighted spin echo (SE) axial MRI images obtained at baseline and at the indicated time points after randomization to the 2.5 mg/cycle dose cohort of OT101. See Figure S6 for details provided for the same images in smaller magnification. (E and F): Review of MRI images by two-to-three independent reviewers (open circle: Reviewer 1; closed circle: Reviewer 2; triangle: Reviewer 3/adjudicator) showed a time-dependent decrease of the 2-D (Panel E) and 3-D (Panels F) size of the target lesion following a significant increase during the early period of pseudo-progression.
Figure 5
Figure 5
Survival Outcome of HGG Patients According to Their Best Overall Responses to OT101. (A): progression-free survival (PFS) outcome of the mITT population. Favorable BOR of CR, PR or stable disease (SD) ≥ 6 months is associated with an improved PFS in R/R HGG patients treated with OT101 monotherapy. Depicted are the PFS curves of the entire 89-patient mITT population as well as 26 favorable responders and 63 non-responders. Patients received no other cancer therapies during the depicted PFS. See also Figure 1 and Table 2. (B) OS outcome of the mITT population. Favorable BOR of CR, PR or SD ≥ 6 months is associated with an improved OS in R/R HGG patients treated with OT101 monotherapy. Depicted are the OS curves of the entire 89-patient mITT population as well as 26 favorable responders and 63 non-responders. See also Table 2.

References

    1. Taal W., Brandsma D., de Bruin H.G., Bromberg J.E., Swaak-Kragten A.T., Sillevis Smitt P.A., van Es C.A., van den Bent M.J. Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer. 2008;113:405–410. doi: 10.1002/cncr.23562.
    1. Stupp R., Taillibert S., Kanner A.A., Kesari S., Steinberg D.M., Toms S.A., Taylor L.P., Lieberman F., Silvani A., Fink K.L., et al. Maintenance Therapy with Tumor-Treating Fields Plus Temozolomide vs. Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015;314:2535–2543. doi: 10.1001/jama.2015.16669.
    1. Herrlinger U., Tzaridis T., Mack F., Steinbach J.P., Schlegel U., Sabel M., Hau P., Kortmann R.D., Krex D., Grauer O., et al. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): A randomised, open-label, phase 3 trial. Lancet. 2019;393:678–688. doi: 10.1016/S0140-6736(18)31791-4.
    1. Jain K.K. A critical overview of targeted therapies for glioblastoma. Front. Oncol. 2018;8 doi: 10.3389/fonc.2018.00419.
    1. Merkel A., Soeldner D., Wendl C., Urkan D., Kuramatsu J.B., Seliger C., Proescholdt M., Eyupoglu I.Y., Hau P., Uhl M. Early postoperative tumor progression predicts clinical outcome in glioblastoma—implication for clinical trials. J. Neurooncol. 2017;132:249–254. doi: 10.1007/s11060-016-2362-z.
    1. Stupp R., Hegi M.E., Mason W.P., van den Bent M.J., Taphoorn M.J., Janzer R.C., Ludwin S.K., Allgeier A., Fisher B., Belanger K., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–466. doi: 10.1016/S1470-2045(09)70025-7.
    1. Miller J.J., Wen P.Y. Emerging targeted therapies for glioma. Expert Opin. Emerg. Drugs. 2016;21:441–452. doi: 10.1080/14728214.2016.1257609.
    1. Carlsson S.K., Brothers S.P., Wahlestedt C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol. Med. 2014;6:1359–1370. doi: 10.15252/emmm.201302627.
    1. Lieberman F. Glioblastoma update: Molecular biology, diagnosis, treatment, response assessment, and translational clinical trials. F1000Research. 2017;6:1892. doi: 10.12688/f1000research.11493.1.
    1. Ostrom Q.T., Gittleman H., Xu J., Kromer C., Wolinsky Y., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013. Neuro Oncol. 2016;18(Suppl. 5):v1–v75. doi: 10.1093/neuonc/now207.
    1. Chang S.M., Theodosopoulos P., Lamborn K., Malec M., Rabbitt J., Page M., Prados M.D. Temozolomide in the treatment of recurrent malignant glioma. Cancer. 2004;100:605–611. doi: 10.1002/cncr.11949.
    1. Desjardins A., Gromeier M., Herndon J.E., Beaubier N., Bolognesi D.P., Friedman A.H., Friedman H.S., McSherry F., Muscat A.M., Nair S., et al. Recurrent Glioblastoma Treated with Recombinant Poliovirus. New Engl. J. Med. 2018;379:150–161. doi: 10.1056/NEJMoa1716435.
    1. Chandramohan V., Bao X., Yu X., Parker S., McDowall C., Yu Y.R., Healy P., Desjardins A., Gunn M.D., Gromeier M., et al. Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations. J. Immunother. Cancer. 2019;7:142. doi: 10.1186/s40425-019-0614-0.
    1. Han J., Alvarez-Breckenridge C.A., Wang Q.E., Yu J. TGF-β signaling and its targeting for glioma treatment. Am. J. Cancer Res. 2015;5:945.
    1. Kjellman C., Olofsson S.P., Hansson O., Von Schantz T., Lindvall M., Nilsson I., Salford L.G., Sjögren H.O., Widegren B. Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. Int. J. Cancer. 2000;89:251–258. doi: 10.1002/1097-0215(20000520)89:3<251::AID-IJC7>;2-5.
    1. Hau P., Jachimczak P., Bogdahn U. Treatment of malignant gliomas with TGF-beta2 antisense oligonucleotides. Expert Rev. Anticancer Ther. 2009;9:1663–1674. doi: 10.1586/era.09.138.
    1. Vallières L. Trabedersen, a TGFβ2-specific antisense oligonucleotide for the treatment of malignant gliomas and other tumors overexpressing TGFβ2. IDrugs. 2009;12:445–453.
    1. Fakhrai H., Dorigo O., Shawler D.L., Lin H., Mercola D., Black K.L., Royston I., Sobol R.E. Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. Proc. Natl. Acad. Sci. USA. 1996;93:2909–2914. doi: 10.1073/pnas.93.7.2909.
    1. Frei K., Gramatzki D., Tritschler I., Schroeder J.J., Espinoza L., Rushing E.J., Weller M. Transforming growth factor-β pathway activity in glioblastoma. Oncotarget. 2015;6:5963–5977. doi: 10.18632/oncotarget.3467.
    1. Roy L.-O., Poirier M.-B., Fortin D. Transforming growth factor-beta and its implication in the malignancy of gliomas. Target. Oncol. 2015;10:1–14. doi: 10.1007/s11523-014-0308-y.
    1. Peñuelas S., Anido J., Prieto-Sánchez R.M., Folch G., Barba I., Cuartas I., García-Dorado D., Poca M.A., Sahuquillo J., Baselga J., et al. TGF-beta Increases Glioma-Initiating Cell Self-Renewal through the Induction of LIF in Human Glioblastoma. Cancer Cell. 2009;15:315–327. doi: 10.1016/j.ccr.2009.02.011.
    1. Bruna A., Darken R.S., Rojo F., Ocaña A., Peñuelas S., Arias A., Paris R., Tortosa A., Mora J., Baselga J., et al. High TGFβ-Smad Activity Confers Poor Prognosis in Glioma Patients and Promotes Cell Proliferation Depending on the Methylation of the PDGF-B Gene. Cancer Cell. 2007;11:147–160. doi: 10.1016/j.ccr.2006.11.023.
    1. Brooks W.H., Netsky M.G., Normansell D.E., Horwitz D.A. Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor. J. Exp. Med. 1972;136:1631–1647. doi: 10.1084/jem.136.6.1631.
    1. Kuppner M.C., Hamou M.F., Sawamura Y., Bodmer S., De Tribolet N. Inhibition of lymphocyte function by glioblastoma-derived transforming growth factor beta 2. J. Neurosurg. 1989;71:211–217. doi: 10.3171/jns.1989.71.2.0211.
    1. Hau P., Jachimczak P., Schlingensiepen R., Schulmeyer F., Jauch T., Steinbrecher A., Brawanski A., Proescholdt M., Schlaier J., Buchroithner J., et al. Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: From preclinical to phase I/II studies. Oligonucleotides. 2007;17:201–212. doi: 10.1089/oli.2006.0053.
    1. Krichevsky A.M., Uhlmann E.J. Oligonucleotide Therapeutics as a New Class of Drugs for Malignant Brain Tumors: Targeting mRNAs, Regulatory RNAs, Mutations, Combinations, and Beyond. Neurotherapeutics. 2019;16:319–347. doi: 10.1007/s13311-018-00702-3.
    1. Schlingensiepen R., Goldbrunner M., Szyrach M.N., Stauder G., Jachimczak P., Bogdahn U., Schulmeyer F., Hau P., Schlingensiepen K.H. Intracerebral and intrathecal infusion of the TGF-beta2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: Toxicology and safety. Oligonucleotides. 2005;15:94–104. doi: 10.1089/oli.2005.15.94.
    1. Bogdahn U., Hau P., Stockhammer G., Venkataramana N.K., Mahapatra A.K., Suri A.A., Balasubramaniam A., Nair S., Oliushine V., Parfenov V., et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: Results of a randomized and controlled phase IIb study. Neuro-Oncol. 2011;13:132–142. doi: 10.1093/neuonc/noq142.
    1. Tauriello D.V., Palomo-Ponce S., Stork D., Berenguer-Llergo A., Badia-Ramentol J., Iglesias M., Sevillano M., Ibiza S., Cañellas A., Hernando-Momblona X., et al. TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554:538–543. doi: 10.1038/nature25492.
    1. Ganesh K., Massagué J. TGF-β Inhibition and Immunotherapy: Checkmate. Immunity. 2018;48:626–628. doi: 10.1016/j.immuni.2018.03.037.
    1. Mariathasan S., Turley S.J., Nickles D., Castiglioni A., Yuen K., Wang Y., Kadel III E.E., Koeppen H., Astarita J.L., Cubas R., et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–548. doi: 10.1038/nature25501.
    1. Thomas D.A., Massagué J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8:369–380. doi: 10.1016/j.ccr.2005.10.012.
    1. Han Z., Kang D., Joo Y., Lee J., Oh G.H., Choi S., Ko S., Je S., Choi H.J., Song J.J. TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade. Exp. Mol. Med. 2018;50:162. doi: 10.1038/s12276-018-0189-8.
    1. Ellingson B.M., Wen P.Y., Cloughesy T.F. Evidence and context of use for contrast enhancement as a surrogate of disease burden and treatment response in malignant glioma. Neuro-Oncol. 2017;20:457–471. doi: 10.1093/neuonc/nox193.
    1. Kruser T.J., Mehta M.P., Robins H.I. Pseudoprogression after glioma therapy: A comprehensive review. Expert Rev. Neurother. 2013;13:389–403. doi: 10.1586/ern.13.7.
    1. Macdonald D.R., Cascino T.L., Schold S.C., Jr., Cairncross J.G. Response criteria for phase II studies of supratentorial malignant glioma. J. Clin. Oncol. 1990;8:1277–1280. doi: 10.1200/JCO.1990.8.7.1277.
    1. Huang R.Y., Rahman R., Ballman K.V., Felten S.J., Anderson S.K., Ellingson B.M., Nayak L., Lee E.Q., Abrey L.E., Galanis E., et al. The Impact of T2/FLAIR Evaluation per RANO Criteria on Response Assessment of Recurrent Glioblastoma Patients Treated with Bevacizumab. Clin. Cancer Res. 2016;22:575–581. doi: 10.1158/1078-0432.CCR-14-3040.
    1. Jahangiri A.J., Chin A.T., Flanigan P.M., Chen R., Bankiewicz K., Aghi M.K. Convection-enhanced delivery in glioblastoma: A review of preclinical and clinical studies. J. Neurosurg. 2017;126:191–200. doi: 10.3171/2016.1.JNS151591.
    1. Zhou Y., Peng Z., Seven E.S., Leblanc R.M. Crossing the blood-brain barrier with nanoparticles. J. Control Release. 2018;270:290–303. doi: 10.1016/j.jconrel.2017.12.015.
    1. Formicola B., Dal Magro R., Montefusco-Pereira C.V., Lehr C.M., Koch M., Russo L., Grasso G., Deriu M.A., Danani A., Bourdoulous S., et al. The synergistic effect of chlorotoxin-mApoE in boosting drug-loaded liposomes across the BBB. J. Nanobiotechnol. 2019;17:115. doi: 10.1186/s12951-019-0546-3.
    1. Mainprize T., Lipsman N., Huang Y., Meng Y., Bethune A., Ironside S., Heyn C., Alkins R., Trudeau M., Sahgal A., et al. Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study. Sci. Rep. 2019;9:321. doi: 10.1038/s41598-018-36340-0.
    1. Idbaih A., Canney M., Belin L., Desseaux C., Vignot A., Bouchoux G., Asquier N., Law-Ye B., Leclercq D., Bissery A., et al. Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. Clin. Cancer Res. 2019;25:3793–3801. doi: 10.1158/1078-0432.CCR-18-3643.
    1. Asquier N., Bouchoux G., Canney M., Martin C., Law-Ye B., Leclercq D., Chapelon J.Y., Lafon C., Idbaih A., Carpentier A. Blood-brain barrier disruption in humans using an implantable ultrasound device: Quantification with MR images and correlation with local acoustic pressure. J. Neurosurg. 2019:1–9. doi: 10.3171/2018.9.JNS182001.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅