Understanding biological activity, tumor response and pseudoprogression in a phase-IIb study of MDNA55 in adults with recurrent or progressive glioblastoma (GB)

Abstract

Background: MDNA55, a novel Interleukin-4 empowered cytokine fused to Pseudomonas exotoxin, binds to IL-4 receptor (IL-4R) overexpressed by GB and immunosuppressive cells of the tumor microenvironment. Understanding biological effects ofMDNA55 and defining their time course requires multi-modal imaging. Consecutive increases in tumor size defined by Response Assessment in Neuro- Oncology (RANO) can result in premature withdrawal of subjects prior to evaluation of clinical benefit. Standard tumor response tools need optimizing for localized immunotherapies to capture delayed treatment benefit. Methods:MDNA55-05 is a 52 subject, open-label, non-randomized, study of intratumoral delivery of≥240 lgMDNA55 via≥ 4 catheters in a single treatment in GB at 1st or 2nd recurrence, tumors≥4 cm.MultimodalityMRI determines tissue response and disease status usingRANO-based criteria, combining contrast-enhanced and perfusion imaging. Results: 27 subjects,median age 51 (35 - 77) received 18 - 180mgMDNA55. Prior treatments included surgery (N=26), radiation (N=25) and temozolomide (N=25). Review of some early post-treatmentMRIs showextensive changes to enhancement which could increase for up to 120 days then take another 6months to resolve.Multi-modal MRI helps differentiate changes due to progression fromlocal tissue reactions (pseudoprogression). Response patterns seen include early progression, early onset response and delayed onset response.Withdrawal of subjects without differentiating pseudoprogression fromtrue progression can preclude the ability to fully assess therapeutic effect. A refined MDNA55 evaluation regimen consisting ofmulti-modalMRI and/or biopsies has been implemented to optimize the chance for increased therapeutic benefit. Conclusions: These findings show biologic activity ofMDNA55 in recurrent GB with appearances on imaging suggestive of disease control in some subjects. We illustrate how supportive diagnostic modalities are required for accurate response assessments and argue the importance of refining overall response tools according to treatment type.