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In addition to providing a pro-inflammatory immune response together with PD-L1 upregulation in the tumor microenvironment, poxvirus-based active immunotherapy resulted in increased numbers of CD8 T cells expressing intermediate levels of PD-1 (PD-1mid). PD-1mid T cells are generally considered more potent at lysing target cells and producing higher amounts of IFNγ and TNFα than PD-1hi cells . In contrast, there were significantly more CD8 T cells that were PD-1hi in the control group. PD-1hi T cells are generally defective in their ability to produce cytokines against target cells and are unable to be rescued by PD-1 immune checkpoint blockade . Importantly, the induction of this functional immune response characterized by activated T cells expressing PD-1mid and PD-L1 expression in the tumor microenvironment provided the foundation for synergistic therapy by combination with PD-1 axis blockade. Importantly, it also allowed for the reduction in the dose of anti-PD-1 monoclonal antibody used.

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Conversely, without an endogenous anti-cancer T cell immune response, as presumed in cancer patients harboring PD-L1neg/low tumors, the immune checkpoint blockade is unfocused and not expected to confer significant clinical benefit . We hypothesized that poxvirus-based immunotherapy would drive antigen-specific T cells to the tumor, concomitant with IFNγ production, thus kryptovaluta inducing PD-L1 expression in the tumor microenvironment. Therefore, this otherwise productive immune response would be enabled into synergistic anti-tumor efficacy when combined with PD-1 axis blockade. These data corroborate evidence from preclinical studies demonstrating that tumors do not upregulate PD-L1 expression in mice lacking T cells or in IFNγ-knockout mice .

These data support the clinical investigation of this triple therapy regimen, especially in cancer patients harboring PD-L1neg/low tumors unlikely to benefit from immune checkpoint blockade alone. Poxvirus-based active immunotherapy results in significant antitumor immunity characterized by robust CD8 T cell infiltration of the tumor . The studies in this report show that this is also accompanied by significant upregulation of PD-L1 expression in the tumor microenvironment, a known adaptive resistance mechanism that occurs in response to IFNγ produced by tumor-infiltrating T cells . When MVA-BN-HER2 immunotherapy was combined with PD-1 blockade, synergistic anti-tumor efficacy was observed, and in 45% of mice the tumors regressed completely.

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LINN's production will increase substantially, its liquids exposure is enhanced, and Berry's portfolio of long-lived assets with low depletion rates fits perfectly with LINN's upstream exploration and production business model. Not only does the Berry acquisition make great sense from an operational standpoint, but LINN and LinnCo investors are likely to see immediate benefits. LINN's hefty 10% distribution will be well-covered by distributable cash flow. And, management has long maintained its intention to increase its payout to $3.08 per unit of LINN and share of LinnCo. This has not happened yet, but it's an exciting possibility that could materialize once the integration of Berry is under way. PD-L1 expression in tumors following PANVAC poxvirus-based immunotherapy in an experimental lung metastasis model.

Why LINN Energy Is a Solid Buy After Closing the Berry Petroleum Acquisition

Early studies showed that LAG-3 affects both CD4 and CD8 T cell function, and plays a role in conventional T cell suppression by Tregs [25–27]. Recently, direct suppression of CD8 T cells by LAG-3 was hypothesized to occur though binding of galectin-3 to glycosylated LAG-3, resulting in cross-linking and activation of the LAG-3 signaling complex . LAG-3 acts independently of and complementary to the PD-1 pathway, and may still inhibit T cell activity when the PD-1 pathway is blocked.

These data corroborate previous findings of antigen spread T cell responses in pre-clinical and clinical studies with poxvirus-based active immunotherapies targeting HER-2, CEA, or PSA . Importantly, these findings further highlight the plasticity and long term durability of productive T cell immunity once tumor-specific killing has been activated. The preclinical data presented here demonstrate the curative potential of poxvirus–based active immunotherapy in combination with dual checkpoint inhibition using anti-PD1 and anti-LAG-3 antibodies and warrant clinical investigation. In fact, poxvirus-based immunotherapy could be the foundation for improving efficacy of cancer immunotherapy therapy employing immune checkpoint inhibitors in general. Men with metastatic castration resistant prostate cancer were treated with the poxvirus-based active immunotherapy PROSTVAC and escalating doses of the immune checkpoint inhibitor Ipilimumab (anti-CTLA-4) in a Phase 1 trial .

While these mechanisms are important to restrict auto-immunity, they can also hinder the development, persistence, and function of desired anti-cancer immunity. Antibodies to block immune checkpoint molecules are being developed and in some indications, approved for clinical use to reverse or prevent the suppression of anti-cancer T cell immune responses . Monotherapy with immune checkpoint blockade has yielded remarkable rapid and durable clinical benefit for some cancer patients, ushering a new era of immuno-oncology for cancer treatment.

The preclinical data presented here suggest that these patients may benefit from PD-1 axis blockade if combined with poxvirus-based active immunotherapies that provoke a productive tumor-infiltrating CD8 T cell response. These data further suggest that the evolution of tumors from PD-L1neg/low to PD-L1hi may be useful as a biomarker for the emergence of productive anti-tumor T cell immunity. Antigen spread is thought to play a critical role in successful immunotherapy as the immune system adapts to target novel tumor antigens as well as restricts tumor evasion to therapy.