Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to molecularly profile tumors both at diagnosis and at relapse and the co-incident progress in the field of radiogenomics could potentially pave the way for a more personalized approach to radiation treatment in contrast to the current ‘‘one size fits all’’ paradigm. Few clinical trials to date have shown an improved clinical outcome when combining targeted agents with radiation therapy, however, most have failed to show benefit, which is arguably due to limited preclinical data. Several key molecular pathways could theoretically enhance therapeutic effect of radiation when rationally targeted either by directly enhancing tumor cell kill or indirectly through the abscopal effect of radiation when combined with novel immunotherapies. The timing of combining molecular targeted therapy with radiation is also important to determine and could greatly affect the outcome depending on which pathway is being inhibited.

Radiodynamic Therapy Using TAT Peptide-Targeted Verteporfin-Encapsulated PLGA Nanoparticles

Radiodynamic therapy (RDT) is a recent extension of conventional photodynamic therapy, in which visible/near infrared light irradiation is replaced by a well-tolerated dose of high-energy X-rays. This enables greater tissue penetration to allow non-invasive treatment of large, deep-seated tumors. We report here the design and testing of a drug delivery system for RDT that is intended to enhance intra- or peri-nuclear localization of the photosensitizer, leading to DNA damage and resulting clonogenic cell kill. This comprises a photosensitizer (Verteporfin, VP) incorporated into poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) that are surface-functionalized with a cell-penetrating HIV trans-activator of transcription (TAT) peptide. In addition to a series of physical and photophysical characterization studies, cytotoxicity tests in pancreatic (PANC-1) cancer cells in vitro under 4 Gy X-ray exposure from a clinical 6 MV linear accelerator (LINAC) showed that TAT targeting of the nanoparticles markedly enhances the effectiveness of RDT treatment, particularly when assessed by a clonogenic, i.e., DNA damage-mediated, cell kill.

Clinical Usage of Tissue Electrical Conductivity during the Electroporation: An Essential and Useful Factor

Electric field intensity at each point is responsible for pore creation in the cell membrane during the electroporation process. These pores can increase the tissue electrical conductivity in the electroporation. Changes in electrical conductivity through the electroporation is a useful factor for imaging and tracking of electroporation inside the body. Electrical conductivity is set to become a vital factor for accurate estimation of the electric field and cell kill probability distribution in the course of electroporation for treatment planning purposes. Therefore, for more accurate treatment, tissue electrical conductivity changes due to electroporation should be considered in the treatment planning system. This paper describes the advantages of tissue electrical conductivity as a useful factor in the clinic.

A Phase 1 Multicenter Open-Label Study of Escalating Doses of the Novel Anti-CD20-Targeting Engineered Toxin Body MT-3724 in Subjects with Relapsed or Refractory Mantle Cell Lymphoma

Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation by SLT-A of ribosomes. MT-3724 represents a novel ETB modality comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A, is capable of efficient internalization once bound to CD20 and can induce potent direct cell-kill via enzymatic ribosome inactivation. In a Phase 1/1b dose escalation/expansion study of MT-3724 monotherapy in subjects with heavily pretreated (including CD20 monoclonal antibodies) relapsed or refractory B-cell non-Hodgkin lymphoma (r/rNHL) the most common grade ≥3 treatment-related adverse events were myalgia and neutropenia (n=3 each). Dose-limiting toxicities (DLTs) were indicative of innate immune response. In subjects with negative rituximab serum concentrations there was a 38% objective response rate (Hamlin et al. ASH 2019). MT-3724 is currently being studied in five ongoing (three actively recruiting, two in development) Phase 2 studies for r/rNHL. This study will evaluate the safety, tolerability, recommended phase 2 dose (RP2D), efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of MT-3724 in two cohorts of subjects with r/r mantle cell lymphoma (r/rMCL). Study Design and Methods: This phase 1, multicenter, open-label, single arm study will include adults ≥18 yrs with histologically confirmed r/rMCL (histology plus expression of Cyclin D1 in association with CD20 and CD5 or evidence of t(11:14)) who have received ≥2 prior systemic therapies (including anti-CD20 antibody alone or in combination with other agents) and have ≥1 measurable lesion (Lugano criteria). Subjects with CNS involvement or recent treatment with rituximab (within 84 days of study initiation; if received within 12-37 weeks of start of treatment, serum rituximab level must be confirmed to be negative [<500 ng/mL]), obinutuzumab (within 184 days), or ofatumumab (within 88 days) will be excluded. The washout period for these anti-CD20 antibodies, based on published half-life data for these agents, is required due to direct binding competition with MT-3724 for the same CD20 epitope. The primary objective is to evaluate safety and determine the RP2D of MT-3724 in subjects with r/rMCL. Secondary objectives include overall response rate based on the Lugano criteria as determined by the investigators, duration of response, disease control rate, progression-free survival, overall survival, PK, PD, and immunogenicity. An exploratory endpoint will assess if responders become eligible for potentially curative therapy (rate of bridge-to-hematopoietic stem cell transplantation or bridge-to-chimeric antigen receptor T-cell therapy). Subjects will receive escalating doses of MT-3724 as a one hr IV infusion in cycle (C) 1 on Days 1, 4, 8, 11, 18, and 25. In C2+, subjects will receive the highest MT-3724 dose on Days 1, 8, 15, and 22 of a 28-day cycle. Two sequential cohorts will be studied. The study will be initiated with Cohort 1 to evaluate DLTs during the first 42 days of therapy. Subjects will have a dose increase only if they do not experience DLTs and dose reductions will be permitted for treatment-related toxicities. If Cohort 1 is deemed tolerable, Cohort 2 (higher doses) will begin; if Cohort 1 dosing is not tolerable, Cohort 0 (lower doses) will begin (Table 1). A Bayesian optimal interval design will be used to identify the RP2D more accurately (target toxicity rate φ=0.3). Enrollment is anticipated to begin in December 2020. Disclosures Wang: Juno:Consultancy, Research Funding;Dava Oncology:Honoraria;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;InnoCare:Consultancy;MoreHealth:Consultancy;Targeted Oncology:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;Oncternal:Consultancy, Research Funding;Pulse Biosciences:Consultancy;Molecular Templates:Research Funding;OncLive:Honoraria;Verastem:Research Funding;Acerta Pharma:Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;BioInvent:Research Funding;Guidepoint Global:Consultancy;VelosBio:Research Funding;Loxo Oncology:Consultancy, Research Funding;Lu Daopei Medical Group:Honoraria;Nobel Insights:Consultancy;Beijing Medical Award Foundation:Honoraria.Burnett:Molecular Templates, Inc.:Current Employment.Strack:Molecular Templates, Inc.:Current Employment.

A numerical study on the effect of conductivity change in cell kill distribution in irreversible electroporation

Introduction: irreversible electroporation (IRE) is a tissue ablation technique and physical process used to kill the undesirable cells. In the IRE process by mathematical modelling we can calculate the cell kill probability and distribution inside the tissue. The purpose of the study is to determine the influence of electric conductivity change in the IRE process into the cell kill probability and distribution.Methods: cell death probability and electric conductivity were calculated with COMSOL Multiphysics software package. 8 pulses with a frequency of 1 Hz, pulse width of 100 µs and electric field intensity from 1000 to 3000 V/Cm with steps of 500 V/Cm used as electric pulses.Results: significantly, the electrical conductivity of tissue will increase during the time of pulse delivery. According to our results, electrical conductivity increased with an electric field intensity of pulses. By considering the effect of conductivity change on cell kill probability, the cell kill probability and distribution will change.Conclusion: we believe that considering the impact of electric conductivity change on the cell kill probability will improve the accuracy of treatment outcome in the clinic for treatment with IRE.

A phase II study of MT-3724, a novel CD20-targeting engineered toxin body, to evaluate safety, pharmacodynamics, and efficacy in subjects with relapsed or refractory diffuse large B-cell lymphoma.

TPS8074 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-3724 represents a novel ETB modality comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A. It is capable of efficient internalization once bound to CD20 and can induce potent direct cell-kill via enzymatic ribosome inactivation. MT-3724 is currently being studied in three ongoing Phase 2 studies for relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). Methods: The primary objective of this single-arm, Phase 2 study (NCT02361346) is to determine the efficacy of MT-3724 monotherapy in r/rDLBCL based on overall response rate (ORR), defined as the proportion of subjects with a complete/partial response according to the Lugano criteria, as assessed by independent, central review. Key secondary objectives include safety, progression-free survival, investigator‐assessed ORR, duration of response, overall survival, and pharmacodynamics. Adverse events will be assessed and documented according to Common Terminology Criteria for Adverse Events version 5.0. Key eligibility criteria include adult subjects with histologically confirmed, r/rDLBCL, with ≥2 prior standard of care systemic NHL treatment regimens, and ≥1 measurable lesion. As rituximab and other CD20-targeting antibodies compete with MT-3724 for the same CD20 domain, minimum washout periods from these agents must be observed. Subjects remain eligible post stem cell transplant or chimeric antigen receptor T-cell therapy. Subjects will receive 50 µg/kg MT-3724 IV over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. The anticipated sample size is N = 100. Interim analyses will be performed to confirm minimum efficacy thresholds based on the encouraging data observed in the completed phase 1 portion of the study [Hamlin et al. Blood 2019;134(Suppl 1):4098]. Multiple global sites are enrolling subjects. Clinical trial information: NCT02361346 .

Synergy between Photodynamic Therapy and Dactinomycin Chemotherapy in 2D and 3D Ovarian Cancer Cell Cultures

In this study we explored the efficacy of combining low dose photodynamic therapy using a porphyrin photosensitiser and dactinomycin, a commonly used chemotherapeutic agent. The studies were carried out on compressed collagen 3D constructs of two human ovarian cancer cell lines (SKOV3 and HEY) versus their monolayer counterparts. An amphiphilc photosensitiser was employed, disulfonated tetraphenylporphine, which is not a substrate for ABC efflux transporters that can mediate drug resistance. The combination treatment was shown to be effective in both monolayer and 3D constructs of both cell lines, causing a significant and synergistic reduction in cell viability. Compared to dactinomycin alone or PDT alone, higher cell kill was found using 2D monolayer culture vs. 3D culture for the same doses. In 3D culture, the combination therapy resulted in 10 and 22 times higher cell kill in SKOV3 and HEY cells at the highest light dose compared to dactinomycin monotherapy, and 2.2 and 5.5 times higher cell kill than PDT alone. The combination of low dose PDT and dactinomycin appears to be a promising way to repurpose dactinomycin and widen its therapeutic applications.