SITC Abstracts out! 018 Abstract Travel Award Recipient
TLR9 agonist harnesses innate immunity to drive tumor‐infiltrating T cell expansion in distant lesions in a phase 1/2 study of intratumoral IMO‐2125+ipilimumab in anti‐ PD1 refractory melanoma patients
Cara Haymaker1, Marc Uemura1, Wen‐Jen Hwu1, Ravi Murthy1, Marihella James1, Ankit Bhatta1, Salah Eddine Bentebibel1, Julie Brevard2, James Geib3, Kathryn Lipford2, Mark Cornfeld3, Srinivas Chunduru3, Cassian Yee1, Scott Woodman1, Rodabe Amaria1, Sapna Patel1, Hussein Tawbi1, Isabella Glitza Oliva1, Michael Davies1, Willem Overwijk1, Patrick Hwu1, Chantale Bernatchez1, Adi Diab1
1University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Idera Pharmaceuticals Inc., Cambridge, MA, USA 3Idera Pharmaceuticals, Inc., Exton, PA, USA
Background
While checkpoint inhibitors (CPI) have transformed melanoma treatment, many patients remain refractory. Pre‐clinical models show combination intratumoral IMO‐2125 (TLR9 agonist) with anti‐ CTLA‐4 or anti‐PD‐1 antibody results in improved tumor control compared with either agent alone. We hypothesized that this combination would stimulate local antigen‐presenting cells, resulting in activation of anti‐tumor T cells and distant responses.
Methods
Adults with anti‐PD‐1 refractory, unresectable stage III/IV melanoma were enrolled. IMO‐2125, escalating from 4 – 32 mg is administered under image guidance, intratumorally on weeks 1, 2, 3, 5, 8, and 11 with standard ipilimumab. Biopsies were obtained in both the injected and distant tumor at
baseline, 1 day and 8 weeks (W8) post injection. Immune analyses included phenotypic, activation, and functional characterization of DC subsets and T cells. T‐cell repertoire diversity was evaluated by high‐throughput CDR3 sequencing and changes in gene expression signatures were assessed by NanoString.
Results
Biopsies were obtained from 17 of the 18 subjects enrolled on the IMO‐2125‐ipilimumab arm. Of 15 subjects with post‐baseline disease evaluations, 9 (60%) showed shrinkage in uninjected tumors with an ORR of 33% by RECIST 1.1. Fresh tumor biopsies taken 24h post IMO‐2125 injection demonstrated induction of an IFN‐a‐response gene signature (IRF7) in all patients (p<0.0001), as well as, maturation of the myeloid DC1 subset (CD1c+CD303‐ ) by upregulation of MHC class II (6/12 patients) and upregulation of PD‐L1 on malignant cells (10/14 patients). W8 biopsies of the uninjected tumor lesion reveal the induction of Ki67+ expression by flow cytometry in effector CD8+ T cells in 6 of 7 regressing lesions indicating an abscopal effect of this combination. In 6 patients with both tumor shrinkage and flow cytometry staining of PBMCs, 4 had higher CD8+ T‐cell proliferation in the tumor than in blood on‐treatment. CDR3 sequencing shows that the top 50 clones form a larger proportion of the repertoire at W8 suggesting local proliferation in both lesions, as well as, the specific expansion in the distant lesion of clones shared with the injected site in responders.
Conclusions
Combination IMO‐2125 and ipilimumab therapy is a promising new treatment for anti‐PD‐1 refractory melanoma. We show this treatment strategy to result in a local IFN‐a‐gene signature coupled with mDC1 maturation. Additionally, the hallmark of tumor shrinkage appears to be the presence of Ki67+ CD8+ T cell effector cells in the uninjected tumor and expansion of clones shared between both lesions (abscopal effect). |
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