[Show abstract][Hide abstract] ABSTRACT: The Society for Immunotherapy of Cancer (SITC) has regularly hosted workshops and working groups focused on immunologic monitoring and immune biomarkers. Due to advances in cancer immunotherapy, including positive results from clinical trials testing new agents and combinations, emerging new technologies for measuring aspects of immunity, and novel candidate biomarkers from early phase trials, the SITC Immune Biomarkers Taskforce has reconvened to review the state of the art, identify current hurdles to further success and to make recommendations to the field. Topics being addressed by individual working groups include: (1) validation of candidate biomarkers, (2) identification of the most promising technologies, (3) testing of high throughput immune signatures and (4) investigation of the pre-treatment tumor microenvironment. Resultant recommendations will be published in JITC.
[Show abstract][Hide abstract] ABSTRACT: Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. Here we report safety and clinical activity of avelumab in patients (pts) with previously treated, recurrent or refractory ovarian cancer (NCT01772004).
Materials and Methods: Pts received avelumab at 10mg/kg as a 1-h infusion Q2W until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumours were assessed every 6 wks (RECIST 1.1). Unconfirmed best overall response (BOR) and progression-free survival (PFS) were evaluated and analyses of overall survival are ongoing. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Tumour PD-L1 expression at baseline was assessed by immunohistochemistry.
Results: Seventy-five women with recurrent or refractory stage III-IV ovarian cancer were treated with avelumab. As of 13 Feb 2015, median duration of treatment was 12 wks (range, 2–54), and 8 pts remained on treatment. Median age was 62y (range 38–84), ECOG performance status was 0 [41.3%] or 1 [58.7%], and pts had received a median of 5 lines of prior treatment (range, 2-≥5). Treatment-related treatment-emergent adverse events (TEAEs) of any grade occurred in 52 pts (69.3%); the most common (>10%) were fatigue (12 [16.0%]), chills (9 [12.0%]), nausea (8 [10.7%]), and diarrhoea (8 [10.7%]). There were 6 pts (8.0%) reporting treatment-related grade 3/4 TEAEs (none occurred in more than 1 pt) and no treatment-related grade 5 TEAEs. Objective responses were observed in 8 (10.7%) pts (95%CI: 4.7, 19.9). All were partial responses and 5 (62.5%) were ongoing at data cutoff. Tumour shrinkage by ≥30% in target lesions was observed in 3 additional pts (4.0%); however, these pts did not meet RECIST criteria for response. Stable disease was observed in 33 pts (44.0%). Median PFS was 11.4 wks (95%CI: 6.3, 12.0) and the PFS rate at 24 wks was 17.2% (95%CI: 8.1, 29.2). Tumours were PD-L1+ in 74.6% of evaluable pts (n=67; 1% tumour expression cutoff). The ORR in PD-L1+ pts (n=50) was 12.0% and 5.9% in PD-L1− pts (n=17). OS data are immature at this time.
Conclusions: Avelumab showed an acceptable safety profile and encouraging clinical activity in this largest-to-date cohort of pts with heavily pretreated, advanced ovarian cancer treated with anti-PD-(L)1 therapy. Analysis of PD-L1 expression shows a trend towards better response in PD-L1+ tumours. Additional clinical studies with avelumab as monotherapy and in combination with other agents in this pt population are planned. *Proposed INN.
[Show abstract][Hide abstract] ABSTRACT: Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab (proposed INN) (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. Here we present results from a cohort of patients (pts) with recurrent or refractory ovarian cancer in an ongoing phase Ib study (NCT01772004). Methods: Pts with ECOG PS 0-1 received avelumab at 10 mg/kg Q2W. Best overall response (BOR) and progression-free survival (PFS) were assessed according to RECIST 1.1. Adverse events (AEs) were evaluated by CTCAE v4.0. A prespecified analysis of 23 pts with follow-up of ≥ 2 months showed confirmed and unconfirmed partial responses (PRs), leading to cohort expansion to 75 pts. Results: Seventy-five pts were enrolled from November 2013 to November 2014 (median age 62 [range 38-84]; ECOG PS 0 [41%] or 1 [59%]; median of four prior lines of therapy). As of January 2015, median duration of treatment with avelumab was 10 weeks (range 2-54 weeks), and 27 pts remained on treatment. Efficacy data from the 23 pts followed-up for ≥ 2 months (range 2–8 months) demonstrated 4 pts (17.4%, [95% CI, 5.0%, 38.8%]) achieved an unconfirmed BOR of PR,11 (47.8%) had stable disease, and 2 pts had >30% tumor shrinkage after progression was reported. Median PFS was 11.9 weeks (95% CI, 5.9, not reached), and the PFS rate at 24 weeks was 33.3% (95% CI, 11.5, 57.2). Drug-related treatment-emergent AEs (TEAEs; all grades) were reported in 18 pts (78.3%), and 2 pts (8.7%) experienced grade ≥ 3 drug-related TEAEs (increased lipase  and elevated creatine kinase and autoimmune myositis that led to discontinuation ). No drug-related serious TEAEs occurred. The most commonly reported drug-related TEAEs (> 10%) were fatigue, nausea, and diarrhea. Conclusions: These data represent the largest reported dataset of pts with recurrent ovarian cancer treated with anti-PD-L1 therapy. Avelumab demonstrated an acceptable safety profile and is clinically active in this heavily pretreated ovarian cancer pt population. Clinical trial information: NCT01772004
[Show abstract][Hide abstract] ABSTRACT: Recent studies of tumor lymphocytic immune infiltrates in breast cancer have suggested an improved prognosis associated with increasing levels of tumor-infiltrating lymphocytes (TIL). Triple-negative breast cancer (TNBC) is the breast cancer subtype that has the greatest incidence of patients with a robust tumor immune infiltrate, although it is still a minority of patients. Elevated levels of either intratumoral or stromal T cells are associated with an improved overall survival (OS) and disease-free survival (DFS) in TNBC as compared with other breast cancer subtypes. TNBC may be immunogenic for several reasons. Subtypes of TNBC have a significant number of genetic mutations, and the immune system may see the aberrant proteins encoded by these mutations as foreign. Moreover, TNBC is associated with a prognostic gene signature that also includes B cells. Antibodies secreted by B cells may bind to tumor antigens and amplify the adaptive immune response that has already been initiated in the tumor. New immune modulatory agents, including immune checkpoint inhibitors, have shown activity in immunogenic tumors such as melanoma and bladder cancer and have recently been tested in TNBC. The clinical response rates observed, patterns of response, and adverse event profiles are similar to what has been described in melanoma where this class of agents has already been approved for clinical use in some cases. Lessons learned in assessing the immunogenicity of TNBC, potential mechanisms of immune stimulation, and response to immune modulatory drugs lay the foundation for the development of immune-based therapies in all subtypes of the disease.
[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer is immunogenic and residual tumor volume after surgery is known to be prognostic. Ovarian cancer often follows a recurring-remitting course and microscopic disease states may present ideal opportunities for immune therapies. We sought to establish the immune profile of a murine model of ovarian cancer that allows in vivo tumor imaging and the quantitation of microscopic disease.
Baseline imaging and weight measurements were taken within 1 and 2 weeks after intraperitoneal tumor injection, respectively. Significantly higher photons per second from baseline imaging were first observed 5 weeks after tumor cell injection (p < 0.05) and continued to be significant through 8 weeks after injection (p < 0.01), whereas a significant increase in weight above baseline was not observed until day 56 (p < 0.0001). Expression of luc2 in ID8 cells did not alter the cellular immune microenvironment of the tumor. FOXP3+ T cells were more likely to be detected in the intraepithelial compartment and CD4+ T cells in the stroma as compared to CD3+ T cells, which were found equally in stroma and intraepithelial compartments.
Use of an intraperitoneal tumor expressing a codon-optimized firefly luciferase in an immunocompetent mouse model allows tumor quantitation in vivo and detection of microscopic tumor burdens. Expression of this foreign protein does not significantly effect tumor engraftment or the immune microenvironment of the ID8 cells in vivo and may allow novel immunotherapies to be assessed in a murine model for their translational potential to ovarian cancers in remission or minimal disease after primary cytoreductive surgery or chemotherapy.
Mouse ovarian surface epithelial cells from C57BL6 mice transformed after serial passage in vitro were transduced with a lentiviral vector expressing a codon optimized firefly luciferase (luc2). Cell lines were selected and luc2 expression functionally confirmed in vitro. Cell lines were intraperitoneally (IP) implanted in albino C57BL/6/BrdCrHsd-Tyrc mice and albino B6(Cg)-Tyrc-2 J/J mice for serial imaging. D-luciferin substrate was injected IP and tumors were serially imaged in vivo using a Xenogen IVIS. Tumor take, weights, and luminescent intensities were measured. Immunohistochemistry was performed on tumors and assessed for immune infiltrates in stromal and intraepithelial compartments.
[Show abstract][Hide abstract] ABSTRACT: Although breast cancer has not historically been believed to be an immunogenic tumor, the importance of the role of the tumor immune environment is emerging for both in invasive and preinvasive breast cancer.
[Show abstract][Hide abstract] ABSTRACT: Recent studies in patients with breast cancer suggest the immune microenvironment influences response to therapy. We aimed to evaluate the relationship between growth rates of tumors in common spontaneous mammary tumor models and immune biomarkers evaluated in the tumor and blood. TgMMTV-neu and C3(1)-Tag transgenic mice were followed longitudinally from birth, and MPA-DMBA-treated mice from the time of carcinogen administration, for the development of mammary tumors. Tumor-infiltrating CD4(+) and CD8(+) T-cells, FOXP3(+) T-regulatory cells, and myeloid-derived suppressor cells were assessed by flow cytometry. Serum cytokines were evaluated in subsets of mice. Fine needle aspirates of tumors were collected and RNA was isolated to determine levels of immune and proliferation markers. Age of tumor onset and kinetics of tumor growth were significantly different among the models. Mammary tumors from TgMMTV-neu contained a lower CD8/CD4 ratio than that of other models (p < 0.05). MPA-DMBA-induced tumors contained a higher percentage of FOXP3(+) CD4(+) T-cells (p < 0.01) and MDSC (p < 0.001) compared with the other models. Individuals with significantly slower tumor growth demonstrated higher levels of Type I serum cytokines prior to the development of lesions compared to those with rapid tumor growth. Moreover, the tumors of animals with more rapid tumor growth demonstrated a significant increase in the expression of genes associated with Type II immunity than those with slower-progressing tumors. These data provide a foundation for the development of in vivo models to explore the relationship between endogenous immunity and response to standard therapies for breast cancer.
Breast Cancer Research and Treatment 11/2014; 148(3). DOI:10.1007/s10549-014-3199-9 · 3.94 Impact Factor