Expanding the Reach of Personalized Medicine in Cancer Care: Current Progress and Future Directions of JCO Precision Oncology.

ASCO Editorial Fellows share insights into publication trends and future directions for JCO Precision Oncology.

A big step for MYC-targeted therapies.

The MYC proto-oncogene encodes a master transcriptional regulator that is frequently dysregulated in human cancer. Decades of efforts have failed to identify a MYC-targeted therapeutic, and this is still considered to be a holy grail in drug development. We highlight a recent report by Garralda et al. of a Phase 1 clinical trial of OMO-103 in patients with solid malignancies.

Anti-PD-L1 F(ab) Conjugated PEG-PLGA Nanoparticle Enhances Immune Checkpoint Therapy.

Background: Immune checkpoint therapies are effective in the treatment of a subset of patients in many different cancers. Immunotherapy offers limited efficacy in part because of rapid drug clearance and off-target associated toxicity. PEG-PLGA is a FDA approved, safe, biodegradable polymer with flexible size control. The delivery of immune checkpoint inhibitors such as anti-PD-L1 (α-PD-L1) via PEG-PLGA polymer has the potential to increase bioavailability and reduce immune clearance to enhance clinical efficacy and reduce toxicity. Methods: The Fc truncated F(ab) portion of α-PD-L1 monoclonal antibody (α-PD-L1 mAb) was attached to a PEG-PLGA polymer. α-PD-L1 F(ab)-PEG-PLGA polymers were incubated in oil-in-water emulsion to form a α-PD-L1 F(ab)-PEG-PLGA nanoparticle (α-PD-L1 NP). α-PD-L1 NP was characterized for size, polarity, toxicity and stability. The relative efficacy of α-PD-L1 NP to α-PD-L1 mAb was measured when delivered either intraperitoneally (IP) or intravenously (IV) in a subcutaneous mouse colon cancer model (MC38). Antibody retention was measured using fluorescence imaging. Immune profile in mice was examined by flow cytometry and immunohistochemistry. Results: Engineered α-PD-L1 NP was found to have pharmacological properties that are potentially advantageous compared to α-PD-L1 mAb. The surface charge of α-PD-L1 NP was optimal for both tumor cell uptake and reduced self-aggregation. The modified size of α-PD-L1 NP reduced renal excretion and mononuclear phagocyte uptake, which allowed the NP to be retained in the host system longer. α-PD-L1 NP was non-toxic in vitro and in vivo. α-PD-L1 NP comparably suppressed MC38 tumor growth. α-PD-L1 NP appeared to elicit an increased immune response as measured by increase in germinal center area in the spleen and in innate immune cell activation in the tumor. Finally, we observed that generally, for both α-PD-L1 NP and α-PD-L1 mAb, the IP route was more effective than IV route for tumor reduction. Conclusion: α-PD-L1 NP is a non-toxic, biocompatible synthetic polymer that can extend α-PD-L1 antibody circulation and reduce renal clearance while retaining anti-cancer activity and potentially enhancing immune activation.

Functional redundancy between thymic CD8α+ and Sirpα+ conventional dendritic cells in presentation of blood-derived lysozyme by MHC class II proteins.

We evaluated the presentation of blood-derived protein Ags by APCs in the thymus. Two conventional dendritic cells (cDCs), the CD8α(+)Sirpα(-)CD11c(hi) (CD8α(+) cDC) and the CD8α(-)Sirpα(+)CD11c(hi) (Sirpα(+) cDC), were previously identified as presenting MHC class II bound peptides from hen egg white lysozyme (HEL) injected intravenously. All thymic APCs acquired the injected HEL, with the plasmacytoid dendritic cell being the best, followed by the Sirpα(+) cDC and the CD8α(+) cDC. Both cDCs induced to similar extent negative selection and regulatory T cells in HEL TCR transgenic mice, indicating a redundant role of the two cDC subsets in the presentation of blood-borne HEL. Immature dendritic cells or plasmacytoid dendritic cells were considerably less efficient. Batf3(-/-) mice, with significantly reduced numbers of CD8α(+) cDCs, were not impaired in HEL presentation by I-A(k) molecules of thymic APCs. Lastly, clodronate liposome treatment of TCR transgenic mice depleted blood APCs including Sirpα(+) cDCs without affecting the number of thymic APCs. In such treated mice, there was no effect on negative selection or regulatory T cells in mice when administering HEL, indicating that the T cell responses were mediated primarily by the cDCs localized in the thymus.

Thymus-blood protein interactions are highly effective in negative selection and regulatory T cell induction.

Using hen egg-white lysozyme, the effect of blood proteins on CD4 thymic cells was examined. A small fraction of i.v. injected hen egg-white lysozyme rapidly entered the thymus into the medulla. There it was captured and presented by dendritic cells (DCs) to thymocytes from two TCR transgenic mice, one directed to a dominant peptide and a second to a poorly displayed peptide, both presented by MHC class II molecules I-A(k). Presentation by DC led to negative selection and induction of regulatory T cells, independent of epithelial cells. Presentation took place at very low levels, less than 100 peptide-MHC complexes per DC. Such low levels could induce negative selection, but even lower levels could induce regulatory T cells. The anatomy of the thymus-blood barrier, the highly efficient presentation by DC, together with the high sensitivity of thymic T cells to peptide-MHC complexes, results in blood protein Ags having a profound effect on thymic T cells.