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April 06, 2017

Understating the Molecular Underpinning of Immunotherapies

AACR 2017: Mechanisms Regulating Immune Checkpoint Therapies

Understating the Molecular Underpinning of Immunotherapies

Source: NIH

  • Immunotherapy is still a captivating topic for researchers and clinicians, to which a cursory glance at the itinerary for the recently held 2017 American Association for Cancer Research (AACR) meeting would indicate to even the most nonscientifically inclined person. Yet, this year seemed to be about refinement, improvement, and forward momentum.

    For instance, a presentation entitled “Mechanisms Regulating Immune Checkpoint Therapies” looked at current strategies that could impact patients by utilizing these therapies, as well as new ways to improve current treatments and identify new biomarkers that are associated with response or resistance to checkpoint-inhibition pathways.

    Data from Bristol-Myers Squibb (BMS) was presented for two unique approaches they tested for improving the potency and safety profile of the anti-CTLA-4 antibody ipilimumab, which has been previously approved to treat metastatic melanoma. The first approach the researchers reported on was to enhance the antibody-dependent cellular cytotoxicity (ADCC) activity of ipilimumab in an attempt to increase the potential for regulatory T-cells (Tregs) depletion at the tumor site—effectively increasing the activity of the antibody. By generating an ipilimumab molecule devoid of the monosaccharide fucose (nonfucosylated ipilimumab or ipilimumab-NF), the BMS team was able to increase the activity of the antibody. Data from tests in mice and macaques led the investigators to surmise that ipilimumab antitumor activity could be greatly enhanced through the use of the nonfucosylated form of the antibody.

    The BMS team's second approach was to create a prodrug form of ipilimumab that would only become active after being proteolytically cleaved at the tumor site—reducing the activity of the drug systemically and consequently lowering a number of adverse effects. The scientists generated and tested a prodrug form of the anti-CTLA-4 antibody, which they dubbed ipilimumab-probody Tx. Interestingly, the prodrug had comparable antitumor and Treg depletion activity in mice at the site of the tumor as the standard form of the drug. However, the prodrug-treated mice had reduced levels of activated peripheral Tregs compared to standard ipilimumab-treated mice, even at an eightfold higher dose than is required for antitumor efficacy. This data is consistent with reduced activity of the probody Tx antibody outside the tumor microenvironment—a scenario that could prove immensely beneficial for patients.

    Next, Seishi Ogawa, M.D., Ph.D., from Kyoto University, presented new data on a novel mechanism for evading antitumor immunity in a variety of cancer subtypes. Dr. Ogawa described how structural variations (SVs) that commonly disrupt the 3′ untranslated region (UTR) of the PD-L1—and to lesser extent PD-L2—genes are common among various cancers, such as stomach adenocarcinoma, diffuse large B-cell lymphoma, and adult T-cell leukemia/lymphoma.

    Dr. Ogawa and his team found that these SVs consistently lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3′-untranslated region (UTR). Furthermore, the investigators observed that the disruption of the PD-L1 3′-UTR in mice allowed immune evasion of EG7-OVA thymoma cells with elevated PD-L1 expression in vivo. Dr. Ogawa noted that this mechanism was successfully inhibited by PD-1/PD-L1 blockade—supporting the role of relevant SVs in clonal selection through immune evasion. The Kyoto University investigators are optimistic that a better understanding of these SVs could aid in identifying cancers actively evading antitumor immunity, therefore potentially being used as a novel genetic marker to predict the response to immune checkpoint blockade therapy.

    The presentations switched gears slightly when findings from investigators at the Sidney Kimmel Comprehensive Cancer Center in Baltimore were presented to address how non-small cell lung cancer (NSCLC) alters neoantigen formation during immune checkpoint blockade. The Kimmel team looked to examine the underlying mechanisms of immunotherapy resistance, beginning with a genome-wide analysis of protein coding genes and T-cell receptor (TCR) clonotypes. The genomic search was followed by autologous T-cell activation assays of patients that showed some initial response to immune checkpoint blockade, yet ultimately developed progressive disease. The investigators used a cohort of 42 NSCLC patients treated with either a single PD-1 or combined PD-1 and CTLA4 blockade compound, identifying cases that developed acquired resistance.

    The researchers utilized a multidimensional neoantigen prediction platform to identify peptides that were predicted to elicit an immune response—resulting in the identification of genomic changes that led to the identification of 7 to 18 putative mutation-associated neoantigens within resistant clones. Moreover, the research team developed an approach to assess T-cell response to candidate mutation associated neoantigens (cMANAs), utilizing next-generation sequencing (NGS) TCR-Vb CDR3 regions as a measure of clonality. This NGS method was used to determine the differential abundance of neoantigen-specific T cell clonotypes among expanded T cell populations.

    Through extensive genomic analyses, the Kimmel Cancer scientists were able to identify changes in the genomic landscape of tumors during immune checkpoint blockade. These results lend weight to the notion that resistance is associated with loss of mutations encoding for putative tumor-specific neoantigens. Finally, assuming the antitumor efficacy of checkpoint blockade involves the release of endogenous T-cell responses to tumor antigens generated by coding mutations, the investigators surmise that their findings are consistent with a mechanism of acquired resistance to immune checkpoint blockade that involves therapy-induced immune editing of MANAs.

    The extensiveness to which immunotherapy is being studied by researchers around the global provides a sense of unity that is hard to translate to a patient suffering from cancer. Suffice it to say patients will be at ease once these endeavors begin producing (even more) lifesaving therapies. Here’s hoping that we will be talking about those at the 2018 AACR meeting.

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