Background: Neoantigens arising from somatic mutations are attractive targets for cancer immunotherapy as they may be recognized as foreign by the immune system. RO7198457, a systemically administered RNA-Lipoplex iNeST was designed to stimulate T cell responses against neoantigens. A first-in-human Phase Ib study of RO7198457, in combination with the aPD-L1 antibody atezolizumab is being conducted in patients with locally advanced or metastatic solid tumors. Methods: RO7198457 is manufactured on a per-patient basis and contains up to 20 tumor-specific neoepitopes. Nine doses of RO7198457 were administered i.v. in weekly and bi-weekly intervals during the 12-week induction stage and every 24 weeks during the maintenance stage. Atezolizumab 1200 mg was administered on Day 1 of each 21-day cycle. Results: In total, 132 patients enrolled in cohorts with doses ranging from 15-50 μg RO7198457 in combination with atezolizumab. Most common tumor types were NSCLC, TNBC, melanoma and CRC. The median number of prior therapies was 3 (range 1-11). 39% of patients received prior immunotherapy. Most patients had low levels of PD-L1 expression (93% patients with <5% PD-L1 expression on tumor cells, 79% patients with <5% expression on immune cells). The median number of RO7198457 doses received was 8; 16% of patients discontinued due to PD prior to completing 6 weeks of therapy. The majority of adverse events (AE) were Grade 1-2. AEs occurring in ≥ 15% of patients included infusion related reaction (IRR)/cytokine release syndrome (CRS), fatigue, nausea and diarrhea. IRR/CRS were transient and reversible and presented primarily as Grade 1-2 chills and fever. There were no DLTs. Seven patients (5%) discontinued treatment due to AEs related to study drugs. RO1798457 induced pulsatile release of pro-inflammatory cytokines with each dose, consistent with the innate immune agonist activity of the RNA. RO7198457 induced neoantigen-specific T cell responses were observed in peripheral blood in 37/49 (77%) patients by ex vivo ELISPOT or MHC multimer analysis. Induction of up to 6% MHC multimer-stained CD8+ T-cells with memory phenotype was observed in peripheral blood. RO7198457-induced T cells against multiple neoantigens that were detected in post-treatment tumor biopsies. Of 108 patients who underwent at least one tumor assessment, 9 responded (ORR 8%, including 1 CR) and 53 had SD (49%). Conclusion: RO7198457 in combination with atezolizumab has a manageable safety profile consistent with the mechanisms of action of the study drugs and induces significant levels of neoantigen-specific immune responses. A randomized Ph2 study of RO7198457 1L melanoma patients in combination with pembrolizumab has been initiated, and two randomized clinical trials are planned for the adjuvant treatment of patients with NSCLC and CRC. Citation Format: Juanita S. Lopez, Ross Camidge, Marco Iafolla, Sylvie Rottey, Martin Schuler, Matthew Hellmann, Ani Balmanoukian, Luc Dirix, Michael Gordon, Ryan Sullivan, Brian S. Henick, Charles Drake, Kit Wong, Patricia LoRusso, Patrick Ott, Lawrence Fong, Aglaia Schiza, Jeffery Yachnin, Christian Ottensmeier, Fadi Braiteh, Johanna Bendell, Rom Leidner, George Fisher, Guy Jerusalem, Laura Molenaar-Kuijsten, Marcus Schmidt, Scott A. Laurie, Raid Aljumaily, Achim Rittmeyer, Eelke Gort, Ignacio Melero, Lars Mueller, Rachel Sabado, Patrick Twomey, Jack Huang, Manesh Yadav, Jingbin Zhang, Felicitas Mueller, Evelyna Derhovanessian, Ugur Sahin, Özlem Türeci, Thomas Powles. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT301.

IMPORTANCE Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown.OBJECTIVE To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTSThis randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis.INTERVENTIONS Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18-labeled fluorodeoxyglucose ( 18 F-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles.MAIN OUTCOME AND MEASURES Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery. RESULTSOverall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor-negative tumors than in hormone receptor-positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36; P = .003). Response evaluation with 18 F-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by equal to or greater than 68.7% (median) was associated with pCR (odds ratio, 6.74, 95% CI, 2.75-16.51; P < .001). CONCLUSIONS AND RELEVANCEIn this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1.

Background and aimsMalignant melanoma is an aggressive tumor sensitive for immunotherapy such as checkpoint blockade antibodies. Still, most patients with late stage disease do not respond, and the side effects can be severe. Stimulation of the CD40 pathway to initiate anti-tumor immunity is a promising alternative. Herein, we demonstrate immune profiling data from melanoma patients treated with an adenovirus-based CD40 ligand gene therapy (AdCD40L).MethodsPeripheral blood mononuclear cells and plasma were collected from malignant melanoma patients (n = 15) enrolled in a phase I/IIa study investigating intratumoral delivery of AdCD40L with or without low dose cyclophosphamide. Cells were analyzed by flow cytometry while plasma samples were analyzed by a multi-array proteomics.ResultsAll patients had an increased Teffector/Tregulatory cell ratio post therapy. Simultaneously, the death receptors TNFR1 and TRAIL-R2 were significantly up-regulated post treatment. Stem cell factor (SCF), E-selectin, and CD6 correlated to enhanced overall survival while a high level of granulocytic myeloid-derived suppressor cells (gMDSCs), IL8, IL10, TGFb1, CCL4, PlGF and Fl3t ligand was highest in patients with short survival.ConclusionsAdCD40L intratumoral injection induced desirable systemic immune effects that correlated to prolonged survival. Further studies using CD40 stimulation in malignant melanoma are warranted. Trial registration The 002:CD40L trial “Phase I/IIa AdCD40L Immunogene Therapy for Malignant Melanoma and Other Solid Tumors” (clinicalTrials.gov identifier: NCT01455259) was registered at September 2011

Purpose: This study analyzes the potential of stromal platelet-derived growth factor receptor-beta (PDGFRb) expression as biomarker for radiotherapy (RT) benefit on ipsilateral breast events (IBE) in ductal carcinoma in situ (DCIS). Improved identification of DCIS patients refractory to adjuvant whole-breast RT is needed. Predictive biomarker studies in DCIS have focused on tumor cell features rather than the tumor-associated stroma, despite growing evidence of its influence on therapy efficiency. Experimental Design: Samples from the Swedish randomized radiotherapy DCIS trial (SweDCIS) were subjected to IHC analysis for stromal PDGFRb expression. IBE incidence at 10 years after breast-conserving surgery was the primary endpoint. Interactions between marker and treatment were analyzed. Results: PDGFRb score was predictive for RT benefit with regard to IBE (Pinteraction = 0.002 and Pinteraction = 0.008 adjusted multivariably). Patients of the PDGFRblow group had a strong benefit from RT regarding IBE risk [HR, 0.23; 95% confidence interval (CI), 0.12–0.45; P &lt; 0.001] with an absolute risk reduction of 21% (cumulative risk 7% vs. 28%) at 10 years. No significant risk reduction by RT was observed for patients of the PDGFRbhigh group (HR, 0.83; 0.51–1.34; P = 0.444; cumulative risk 22% vs. 25%). The RT response–predictive effect of stromal PDGFRb was equally strong in analyses for in situ and invasive IBE when analyzed separately (in situ IBE: P = 0.029; invasive IBE: P = 0.044). Conclusions: Results suggest high stromal PDGFRb expression as a novel biomarker identifying DCIS patients who are refractory to standard whole-breast adjuvant RT. The data imply previously unrecognized fibroblast-mediated modulation of radiosensitivity of DCIS, which should be further explored from mechanistic and targeting perspectives.