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Low-dose metronomic cyclophosphamide complements the actions of an intratumoral C-class CpG TLR9 agonist to potentiate innate immunity and drive potent T cell-mediated anti-tumor responses


The cover for issue 68 of Oncotarget features Figure 4, "Gene expression changes to the TME demonstrate sequential development of innate and adaptive immune responses," by Leong, et al.

Intratumoral injection of SD-101 induces significant anti-tumor immunity in preclinical and clinical studies, especially when combined with PD-1 blockade.

Combination therapy generated CD8+ T cell dependent immunity leading to rejection of both non-injected and injected tumors and long-term survival, even in very large tumors.

Dr. Mary J. Janatpour from Dynavax Technologies, Inc., Emeryville, CA 94608,USA said, "It has long been appreciated by cancer researchers that the phenotypic heterogeneity and progressive evolution of malignant tumors minimizes the chance that any agent targeting a single molecular pathway could effectively cure advanced cancer."

Figure 4: Gene expression changes to the TME demonstrate sequential development of innate and adaptive immune responses. (A) CT26 cells were implanted s.c. in both flanks (n=4-5/group). CY (40 mg/kg) was given i.p. and SD-101 (50 μg/injection) was injected into the right flank (injected site). RNA was extracted from tumors as indicated in the experimental schema (A). (B) Number of differentially expressed (DE) genes in the treatment groups that exhibit a log2 fold change >0.6 (>1.5 fold change) and P<0.05 compared to control group at the indicated time points. (C) Venn diagrams of the number of overlapping DE genes of the non-injected tumors between treatment conditions. (D) Heatmap of directed global significance scores (non-injected tumor), which display the extent to which a gene sets' genes are up or down-regulated with the treatments relative to control at that time point. (E) Pathway scores (non-injected tumor), which summarize the data from a pathway's genes with a single score, of select functional pathways. (F) Cell type scores (non-injected tumor), which measure the intratumoral abundance of immune cells using specific gene signatures. Data are mean ± SEM, * compared with control, * compared with SD-101, * compared with CY. * indicates P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001, and **** P ≤ 0.0001.

The authors have previously demonstrated in mouse tumor models that employing the innate immune system to prime a T cell response, in combination with checkpoint blockade, results in deep and durable anti-tumor efficacy.

These high response rates were observed in both injected and non-injected tumor lesions and patients with PD-L1 negative tumors, indicating low levels of basal immune inflammation, responded as well as patients with PD-L1 positive tumors.

Intratumorally administered SD-101 exerts its priming activity and ultimate orchestration of a systemic anti-tumor T cell response through multiple mechanisms.

The production of interferon stimulates tumor cell killing by natural killer cells, with ensuing tumor antigen release, and induces chemokines that attract T cells back to the tumor bed.

Low-dose cyclophosphamide decreases Tregs. Additional impacted biological activities have been described, such as:

  • increased interferon production,
  • induction of immunogenic cell death,
  • increases in effector T cells, and
  • increases in functional NK cells,

...likely to be complementary to SD-101 activity by virtue of modulation of the TME. By administering SD-101 locally, rather than systemically, the researchers demonstrate that localized SD-101 injection combined with systemically administered low-dose cyclophosphamide confers an anti-tumor response at non-injected sites.

The Janatpour research Team concluded that, taken together, the intratumoral SD-101 plus low-dose CY combination may complement existing checkpoint blockade therapies in patients to improve efficacy in the clinic and extend the benefits of immunotherapy to more patients.

Full text - https://doi.org/10.18632/oncotarget.27322

Correspondence to - Mary J. Janatpour - mjanatpour@dynavax.com

Keywords - TLR9, SD-101, cyclophosphamide, immune therapy, innate immunity

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