Combination Of Immunomodulatory Agents Research Articles

Abstract B112: Targeting immunotherapy to the tumor microenvironment using anti-PDL1 VHH

Abstract Cytokines and other immune modulating agents act locally, and delivery of particular immune based therapies to the right cell population in the tumor has been challenging. Many agents have systemic toxicities. Many others fail to arrive in the tumor, and delivering multiple agents to tumor infiltrating lymphocytes is likewise problematic. Pancreatic cancer is the best example of a stroma-rich tumor, where drug delivery often fails. Immunotherapy has shown impressive clinical benefit for many malignancies, particularly for metastatic melanoma; however, pancreatic cancer is among the few cancer types in which anti-CTLA-4 and PD-1 blockade have largely failed. PDAC is fairly average in terms of mutational burden, PDL1 expression, and T cell infiltration, thus the failure to respond to immune checkpoint blockade cannot be explained by these factors. PDAC is uniquely distinguished by a dense stromal reaction, resulting in a nutrient-poor immunosuppressive environment. We hypothesize that targeted delivery of a combination of immunomodulatory agents will change the pancreatic tumor microenvironment to relieve immunosuppression will allow for more effective anti-tumor immune responses. Alpacas and other camelid species generate single domain antibodies, the variable portions of which can be expressed recombinantly and retain the binding properties of full-size antibodies at 1/10th the size. We have generated high-affinity VHHs specific for mouse and human PD-L1. We show by immuno-positron emission tomography (PET) that small VHHs penetrate deeply into orthotopic pancreatic tumors, and can effectively deliver payloads to the tumor interior. Pancreatic tumor cells, whether growing in culture or growing in an orthotopic tumor, express high levels of PD-L1 at baseline. PD-L1 is largely absent from normal tissues; thus we can use PDL1-VHH as a tumor-specific targeting agent. PDL1-VHH was conjugated to the cytokines IL-2 or IFNγ, and we looked for an effect of these reagents in both melanoma and an orthotopic model of pancreatic cancer. Both reagents reduce the growth of B16 tumors in conjunction with an antibody against the melanoma protein TRP1 (TA99). For pancreatic cancer, aPDL1-IL2 treatment showed a 50% reduction in overall tumor burden, an increase in the intratumoral ratio of CD8+ T cells to CD4+Tregs, and increased T cell trafficking to the tumor microenvironment. aPDL1-IFNγ caused a profound reduction in size of both Panc02 and KPC orthotopic tumors, largely by reprogramming intratumoral macrophages. Here we exploit the near-ubiquitous expression of PD-L1 by tumors to focus immune therapies on the tumor microenvironment, and propose that this may be a general technique for enhancing responses to immune therapy, while greatly reducing the risk of systemic toxicities. Citation Format: Michael Dougan, Jessica Ingram, Hidde Ploegh, Stephanie K. Dougan. Targeting immunotherapy to the tumor microenvironment using anti-PDL1 VHH [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B112.

Advances in the Treatment of Metastatic Melanoma: New Immunomodulatory Agents

Antibodies targeting ligand-receptor interactions that control activation and function of immune cell subsets such as dendritic cells (DCs) and in particular T cells have shown substantial promise for the treatment of unresectable or metastatic melanoma. The furthest in development, the antagonist anti-CTLA-4 antibodies, which block a key negative regulator of T-cell activation, have been shown to produce durable clinical responses in a small subset of patients. One of these antibodies, ipilimumab, also prolonged overall survival in two randomized phase III studies, leading to regulatory approval for marketing by the US Food and Drug Administration (FDA). Consistent with its mechanism of action, the major adverse events from anti-CTLA4 stem from immune-mediated inflammatory reactions. Paradigms for the administration of anti-CTLA-4 and newer immunomodulatory agents have evolved to effectively manage the adverse events and also to consider unique patterns and kinetics of tumor response. Early clinical studies of another antagonist antibody, which blocks the co-inhibitory receptor PD-1 on activated T cells, also are showing promising activity in metastatic melanoma. The clinical efficacy of cancer vaccines, which in broad terms also includes intratumorally administered agents designed to increase tumor immunogenicity, is being investigated in ongoing phase III trials, and various new agents are in earlier development, including newer cytokines and T-cell or DC co-stimulatory antibodies, some of which have already demonstrated clinical activity in advanced disease. Current data suggest that focusing development on agents countering immune suppression in the tumor microenvironment or blocking regulatory checkpoints to T-cell activation may have the greatest clinical yield. Combinations of immunomodulatory agents also may improve clinical activity, although possibly at a cost of greater toxicity. A major challenge for the field will be to develop predictive biomarkers of response, and to identify mechanisms of resistance to existing agents that can be addressed in subsequent clinical trials.

Antibody and Immunomodulatory Agents in the Treatment of Indolent Non-Hodgkin’s Lymphoma

Immunomodulatory agents, including cytokines, CpG oligonucleotides, and anti-idiotype vaccines have properties that suggest they have the ability to augment rituximab in the treatment of non-Hodgkin's lymphoma (NHL). Although several clinical trials have shown promising results, no randomized trials of reasonable size have been reported to date, limiting the ability to discern whether combinations of immunomodulatory agents with rituximab impact clinical outcome. Until such trials are mature, we do not recommend using these agents in combination outside of the research setting.

From Acute Pancreatitis to End-Organ Injury: Mechanisms of Acute Lung Injury

Multi-organ dysfunction, and in particular lung injury, is often responsible for the unfavorable outcome of patients with severe acute pancreatitis. Understanding of the mechanisms by which local inflammation in the pancreas leads to end-organ injury is crucial for the development of new therapeutic strategies. A MEDLINE search was performed with the terms "acute pancreatitis," "lung injury," "inflammatory response," "SIRS," and "multi-organ dysfunction." Pertinent articles were selected for analysis. Modulation of the inflammatory response using a combination of immunomodulatory agents may decrease the incidence of severe pancreatitis-related acute lung injury and acute respiratory distress syndrome. Clinical trials are of utmost importance to establish the validity of such strategies.

Antibody and immunomodulatory agents in treatment of indolent non-Hodgkin's lymphoma

Immunomodulatory agents, including cytokines, monoclonal antibodies, and CpG oligonucleotides, have properties that suggest they have the ability to augment rituximab in the treatment of non-Hodgkin's lymphoma. Although several clinical trials have promising results, no randomized trials of reasonable size have been performed to date, limiting the ability to discern whether combinations of immunomodulatory agents with rituximab impact clinical outcome. Until such trials are mature, we do not recommend using these agents in combination outside of the research setting.

Infliximab treatment of Crohn disease ileovesical fistula

Ileovesical fistula is a rare inaugural complication of Crohn disease. Current approaches associate antibiotics, total parenteral nutrition and various combinations of immunomodulatory agents. However, only a minority of fistulas subside under conventional treatment, as most of them ultimately require complex surgery to excise and close the structures involved. We report the case of a 31‐year‐old patient successfully treated by targeting the local production of tumour necrosis factor alpha with infliximab.