Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor

Pre-metastatic and immunological conditioning of the hepatic niche during melanoma progression

The approval of immune checkpoint inhibition (ICI) for advanced melanoma patients heralded a new era in melanoma therapy. ICI is approved as palliative and adjuvant treatment for stage IV and stage III patients, respectively. Neoadjuvant ICI is currently not approved but is investigated in clinical trials for stage II and stage III patients. Liver metastasis, which is detected in ~10-20% of stage IV patients, gained special attention, as it recently evolved as important indicator of treatment resistance to ICI. In this study, the pre-metastatic immunological conditioning of the murine hepatic vascular niche is characterized and compares different ICI treatment regimens (i.e. palliative, adjuvant and neoadjuvant) regarding their efficiency to prevent and treat liver metastasis formation. Hepatic metastases in mice were induced either by intravenous or intrasplenic injection of melanoma cell lines WT31 and B16F10 to assess treatment responses among palliative, adjuvant and neoadjuvant ICI. In the neoadjuvant setting, melanoma cells were also injected intracutaneously to simulate primary cutaneous melanomas. The immune cell composition and activation was comparatively analyzed within the primary tumor, the blood and the liver with FACS, IF/IHC, in situ hybridization and cytokine assays. Hepatic metastasis was similar in extent in mice with intracutaneous melanomas compared to PBS injected controls indicating that a primary melanoma did not induce a pre-metastatic niche with a strong pro- or anti-tumoral phenotype. Naïve adjuvant therapy starting on day 0 showed reduced liver metastases in comparison to late palliative therapy starting on day 9. This was accompanied by increased hepatic infiltration of CD3+ CD8+ T cells in the naïve adjuvant therapy. Neoadjuvant therapy in the presence of a primary cutaneous melanoma showed even less hepatic metastases in comparison to adjuvant therapy. Primary tumors showed a T cell inflamed phenotype in neoadjuvant therapy and an immune excluded phenotype in adjuvant therapy. This was paralleled by increased CD4+ and CD8+ T cells in the peripheral blood in the neoadjuvant therapy. Additionally, hepatic CD4+ T-bet+ T cells significantly increased in neoadjuvant therapy while CD4+ Gata3+ T cells decreased in comparison to adjuvant therapy. Our data indicate that the choice of the therapeutic regimen is an important factor influencing the susceptibility of the hepatic vascular niche to liver metastasis and also therapy response to immune checkpoint inhibition. Neoadjuvant ICI was superior to adjuvant ICI regarding the prevention of liver metastasis formation. Furthermore, the liver showed a more Th1 driven immune response. Increased numbers of CD4+ Gata3+ T cells in the livers of mice in the adjuvant setting indicate a more Th2-driven immune response. Therefore, neoadjuvant ICI may be an excellent option for CM to prevent the spread to distant organs and to help improving the outcome of patients with distant metastases

Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans

Exceptional and Durable Responses to TDM-1 After Trastuzumab Failure for Breast Cancer Skin Metastases: Potential Implications of an Immunological Sanctuary

Breast Cancer (BC) skin metastases represent a challenging clinical scenario. Although they usually arise when other distant metastases are already present, they may also represent a form of locoregional recurrence (LRR). Systemic therapy in this setting may have a role both in case a radical locoregional approach is unfeasible in order to achieve disease control, and as adjuvant strategy after radical removal of cutaneous lesions, in order to prevent or delay subsequent disease spread. Systemic therapy for HER2+ metastatic BC (MBC) currently relies on anti-HER2 targeted agents. In this context TDM1 is an option in trastuzumab-resistant patients.Here we present 2 cases of isolated skin metastases in patients with HER2+ BC progressing during or early after trastuzumab-based therapy, showing impressive responses to TDM1. We hypothesize that the unique properties of skin immune microenvironment may explain the failure of trastuzumab, which exerts its action also through immunological mechanisms, and the subsequent outlier responses to TDM1, that relies on a partially different mechanism of action

Immunotherapy of lung cancer: An update

In Germany lung cancer is the leading cause of cancer-associated death in men. Surgery, chemotherapy and radiation may enhance survival of patients suffering from lung cancer but the enhancement is typically transient and mostly absent with advanced disease; eventually more than 90% of lung cancer patients will die of disease. New approaches to the treatment of lung cancer are urgently needed. Immunotherapy may represent one new approach with low toxicity and high specificity but implementation has been a challenge because of the poor antigenic characterization of these tumors and their ability to escape immune responses. Several different immunotherapeutic treatment strategies have been developed. This review examines the current state of development and recent advances with respect to non-specific immune stimulation, cellular immunotherapy ( specific and non-specific), therapeutic cancer vaccines and gene therapy for lung cancer. The focus is primarily placed on immunotherapeutic cancer treatments that are already in clinical trial or well progressed in preclinical studies. Although there seems to be a promising future for immunotherapy in lung cancer, presently there is not standard immunotherapy available for clinical routine

Current trends in glioblastoma multiforme treatment: radiation therapy and immune checkpoint inhibitors.

Glioblastoma multiforme (GBM) is the most common primary brain cancer. Even with aggressive combination therapy, the median life expectancy for patients with GBM remains approximately 14 months. In order to improve the outcomes of patients with GBM, the development of newer treatments is critical. The concept of using the immune system as a therapeutic option has been suggested for several decades; by harnessing the body's adaptive immune mechanisms, immunotherapy could provide a durable and targeted treatment against cancer. However, many cancers, including GBM, have developed mechanisms that protect tumor cells from being recognized and eliminated by the immune system. For new immunotherapeutic regimens to be successful, overcoming immunosuppression via immune checkpoint signaling should be taken into consideration

A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon

Purpose: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFN-a2b treatment and predictive for survival. Experimental design: We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy. Results: Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021), HLA-C15 (p = 0.025), HLA-C3 (p = 0.014), DRB1*15 (p = 0.005) and CT60*G/G (0.081) were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709), 0.387 (95% CI, 0.169-0.889), 0.449 (95% CI, 0.237-0.851), 1.948 (95% CI, 1.221-3.109) and 1.484 (95% IC, 0.953-2.312) respectively. Conclusion: These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed

Evaluation of a tumor microenvironment-based prognostic score in primary operable colorectal cancer

Purpose: The tumor microenvironment is recognized as an important determinant of progression and outcome in colorectal cancer. The aim of the present study was to evaluate a novel tumor microenvironment–based prognostic score, based on histopathologic assessment of the tumor inflammatory cell infiltrate and tumor stroma, in patients with primary operable colorectal cancer. Experimental Design: Using routine pathologic sections, the tumor inflammatory cell infiltrate and stroma were assessed using Klintrup–Mäkinen (KM) grade and tumor stroma percentage (TSP), respectively, in 307 patients who had undergone elective resection for stage I–III colorectal cancer. The clinical utility of a cumulative score based on these characteristics was examined. Results: On univariate analysis, both weak KM grade and high TSP were associated with reduced survival (HR, 2.42; P = 0.001 and HR, 2.05; P = 0.001, respectively). A cumulative score based on these characteristics, the Glasgow Microenvironment Score (GMS), was associated with survival (HR, 1.93; 95% confidence interval, 1.36–2.73; P < 0.001), independent of TNM stage and venous invasion (both P < 0.05). GMS stratified patients in to three prognostic groups: strong KM (GMS = 0), weak KM/low TSP (GMS = 1), and weak KM/high TSP (GMS = 2), with 5-year survival of 89%, 75%, and 51%, respectively (P < 0.001). Furthermore, GMS in combination with node involvement, venous invasion, and mismatch repair status further stratified 5-year survival (92% to 37%, 93% to 27%, and 100% to 37%, respectively). Conclusions: The present study further confirms the clinical utility of assessment of the tumor microenvironment in colorectal cancer and introduces a simple, routinely available prognostic score for the risk stratification of patients with primary operable colorectal cancer

Immunotherapy, Inflammation and Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR-MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR-MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L)

The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer

Although there is increasing appreciation of the role of the host inflammatory response in determining outcome in patients in colorectal cancer, there has been little concerted effort to favourably manipulate cancer-associated inflammation, either alone or in combination with current oncological treatment. Epidemiological and cardiovascular disease studies have identified aspirin, other nonsteroidal anti-inflammatory drugs and statins as potential chemotherapeutic agents which may manipulate the host inflammatory response to the benefit of the patient with cancer. Similarly, evidence of a chemotherapeutic effect of histamine-2 receptor antagonists, again mediated by an immunomodulatory effect, has previously led to increased interest in their use in gastrointestinal cancer. Extensive pre-clinical data and a limited number of clinical investigations have proposed a direct effect of these agents on tumour biology, with an anti-tumour effect on several of the hallmarks of cancer, including proliferative capacity, evasion from apoptosis and cell cycle regulation, and invasive capability of tumour cells. Furthermore, clinical evidence has suggested a pertinent role in down-regulating the systemic inflammatory response whilst favourably influencing the local inflammatory response within the tumour microenvironment. Despite such compelling results, the clinical applicability of nonsteroidal anti-inflammatory drugs, statins and histamine-2 receptor antagonists has not been fully realised, particularly in patients identified at high risk on the basis of inflammatory parameters. In the present review, we examine the potential role that these agents may play in improving survival and reducing recurrence in patients with potentially curative colorectal cancer, and in particular focus on their effects on the local and systemic inflammatory response