Summary

Immune checkpoint(s) blockade is becoming the therapeutic mainstay in melanoma and lung cancer. Based on these important clinical achievements, immunotherapy with immunomodulating monoclonal antibodies (mAb) is being explored as a new therapeutic modality in most human malignancies, either alone or in combination with other immunomodulating agents. We have provided extensive evidence that the second generation DNA hypomethylating agent (DHA), guadecitabine (SGI-110), plays a promising role in potentiating the immunogenicity
and the immune recognition of human malignancies through the up-regulation of the expression of different immune molecules on cancer cells. These findings led us to hypothesize that DHA could represent ideal partners for immune checkpoint(s) blocking agents to improve their therapeutic efficacy. Here, we studied the expression of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and 2 (PD-L2), and cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) in peripheral blood mononuclear cells of acute myeloid leukemia (AML) patients (N=23), enrolled in a phase 1-2 study with guadecitabine. Patients included in this preliminary analysis were selected based on their responsiveness to therapy. Quantitative RT-PCR analyses showed a constitutive expression
(gene/β-actin molecules >7.5E-05) of PD1, PD-L1, PD-L2 and CTLA-4 in 82.6%, 100%, 47.8% and 8.7% patients, respectively.

Guadecitabine therapy up-regulated (≥2 fold) the expression of PD1, PD-L1, PD-L2 and CTLA-4 in 57.9%, 56.5%, 18.2% and 0% patients, respectively, at any of the time-points investigated during treatment. De novo expression of PD1, PD-L2 and CTLA-4 was observed in 100%, 41.6% and 38.1% of the immune checkpoint(s)-negative patients, respectively.
Though preliminary, these results further support the strong link between epigenetics/DNA methylation and immune response, in cancer patients, and strengthen the therapeutic potential of igenetic immunomodulation, with “consolidated” and emerging immune checkpoint(s) blocking mAb.

View further details below
2016 AACR: Immune checkpoint(s) expression in AML pts enrolled in phase 1-2 study with guadecitabine

Summary

• Guadecitabine(SGI-110) is a novel hypomethylatingdinucleotide of decitabine(DAC) and deoxyguanosinethat is resistant to degradation by cytidine deaminase and results in prolonged in vivo exposure to its active metabolite DAC. The differentiated pharmacokinetic profile offers the potential of improved biological and clinical activity and safety over currently available hypomethylatingagents (HMA).
• We reported previously results from the Phase 1 dose-escalation study in AML and MDS1and the Phase 2 randomized dose-response study in r/r AML patients of SGI-110 given SC at 2 doses (60 and 90 mg/m2) in a 5-day regimen2or at 60 mg/m2in a 10-day regimen.
• Rationale for guadecitabinecombination with immunomodulating agents
  • Tumor Associated Antigens (TAAs) including Cancer Testis Antigens (CTAs) e.g. NY-ESO-1 and MAGE-A are often silenced by hypermethylation
  • Guadecitabine demethylates and induces CTA re-expression rendering the tumor more immunogenic
  • Guadecitabine induces better tumor recognition by immune system (cytotoxic CD8+ T lymphocytes)
  • Clinical correlation between hypermethylationand poor survival reported in Melanoma and Liver Cancer
  • Anecdotal clinical data from patients treated with HMA and immunotherapy
• Guadecitabineimmunomodulatory data
  • Preclinical In vitro Data:
    • Guadecitabine demethylates the promoters and induces the expression of CTAs MAGE-A3, NY-ESO-1 in cancer cell lines
    • Guadecitabine induces tumor recognition by cytotoxic T lymphocytes
  • Preclinical In vivo Data
    • Synergy when guadecitabineis combined with CTLA-4 antibody
  • Clinical Data
    • Guadecitabine achieves dose-dependent demethylation and induction of CTAs (NY-ESO-1; MAGE-A1 and A3) in AML and MDS patients

View further details below
2016 TAT: Guadecitabine (SGI-110), a novel partner in immunotherapy

Summary

• We previously reported results from a multicenter study of guadecitabine randomized to a 5-day regimen at either 60 or 90 mg/m2 in 51 treatment naïve elderly AML patients not eligible for intensive chemotherapy
• There were no significant differences in overall composite complete response (CRc: CR+CRp+CRi) or safety between the two doses; however 14 patients were still on treatment at the time of the prior analysis
• We present here current results on these patients with a median follow-up of 24 months (20.2-33) during which 38 death events occurred in the 51 patients treated (75%)

View further details below
2015 EHA: Late response & OS long term follow up of randomized P2 Study of SGI-110 in elderly AML

Summary

Background : Epigenetic changes, particularly in DNA methylation, have been implicated in acquired resistance to platinum in ovarian cancer (OC). Methods: An ongoing phase I/II multi-institutional clinical trial uses the novel DNA methyltransferase (DNMT) inhibitor guadecitabine (SGI-110) to re-sensitize recurrent platinum resistant OC to carboplatin. Patients enrolled in this trial had recurrent platinum resistant OC and multiple lines of prior therapy. Tumor biopsies were collected at baseline and after two cycles of guadecitabine administered daily for 5 days in low dose (30mg/m2). The goal of the current study was to analyze and integrate global RNA expression and DNA methylation profiles of platinum resistant tumors and to measure genomic and epigenomic changes induced by guadecitabine in tumors. RNA and DNA were extracted from 48 and 57 baseline tumors and analyzed using next generation sequencing (RNA-seq) and Infinium Human Methylation450 (HM450) arrays, respectively. Differential gene expression and DNA methylation profiles were generated and used for Ingenuity Pathway Analysis (IPA) to identify the top altered pathways in response to guadecitabine. Results: Analysis of a limited number of paired samples before and after treatment (n=8) revealed significant changes in global gene expression profiles induced by SGI-110, with 960 altered genes representing immunopathway enrichment including: cytokine production in macrophages and T helper cells by IL-17A and IL-17F, granulocyte /agranulocyte adhesion and inflammation, IL-8 signaling, p38 MAPK signaling, cAMP-mediated signaling, and innate immunity. HM450 analysis showed a greater number of hypermethylated genes in baseline tumors compared to primary OC samples in The Cancer Genome Atlas (TCGA) and demethylation (decreased β-values relative to baseline) of a large number of loci (381 gene promoters) after guadecitabine treatment. IPA analysis of baseline tumor transcriptome and methylome demonstrated significant enrichment in a wide range of pathways associated with cancer, stem cells, inflammation and the immune system. Conclusions: These data suggest that treatment with a DNMT inhibitor induces a reactivation of immune responses in human OC. Correlations between methylation changes and expression profiles are being explored.

View further details below
2015 ASCO: Epigenome and Genome Alterations in Platinum Resistant Ovarian Cancer