Tumors evolve in close interaction with their microenvironment, which encompasses a continual tension between the developing tumor and the host immune system. Clinical trials have shown that appropriate enhancement of a tumor immune response can lead to long-lasting clinical responses and patient benefit. Understanding the contribution of the immune contexture, in addition to the molecular subtype across different tumor indications, is a significant knowledge gap with limited sagacity to drive rational immunotherapy combinations. To better inform clinical studies, we must first strive to understand the multifaceted elements of the tumor-immune interaction, the spatiotemporal interplay of numerous different immune cell types, in conjunction with an understanding of the oncogenic drivers and mutations that may lead to presentation of neoepitopes and could drive changes within the tumor microenvironment. In this review, we discuss the Immunoscore and its probable universal characteristic. The overlay of immune quantification with the molecular segments of disease and how this may benefit identification of patients at high risk of tumor recurrence will be discussed. The Immunoscore may translate to provide a tumor agnostic method to define immune fitness of a given tumor and predict and stratify patients who will benefit from certain therapies (in particular immune therapies) and, ultimately, help save the lives of patients with cancer.

/pdf/the-immunoscore-colon-cancer-and-beyond-55vo116716.pdf

The Immunoscore: Colon Cancer and Beyond

Summary Background Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. Methods The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. Findings Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3–90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. Interpretation Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. Funding AstraZeneca.

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study.

Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II Study

Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC), yet the mechanisms driving benefit are poorly understood. To identify predictors of clinical benefit to ICB, we performed immunogenomic profiling of tumor samples from patients with relapsed SCLC. Tumors of patients who derive clinical benefit from ICB exhibit cytotoxic T-cell infiltration, high expression of antigen processing and presentation machinery (APM) genes, and low neuroendocrine (NE) differentiation. However, elevated Notch signaling, which positively correlates with low NE differentiation, most significantly predicts clinical benefit to ICB. Activation of Notch signaling in a NE human SCLC cell line induces a low NE phenotype, marked by increased expression of APM genes, demonstrating a mechanistic link between Notch activation, low NE differentiation and increased intrinsic tumor immunity. Our findings suggest Notch signaling as a determinant of response to ICB in SCLC.

/pdf/notch-signaling-and-efficacy-of-pd-1-pd-l1-blockade-in-4nwkds6vhj.pdf

Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer.

Despite decades of research, prognosis for SCLC patients remains poor, and treatment options limited. SCLC is an immunogenic tumor with high somatic mutation rates due to tobacco exposure resulting in potential neo-antigens, the presence of suppressed immune responses, and occurrence of paraneoplastic disorders. The use of T cell immune-checkpoint inhibitors (anti-PD1: nivolumab, pembrolizumab; anti-PD-L1: atezolizumab, durvalumab; anti-CTLA-4: ipilimumab, tremelimumab) have shown promising antitumor activity with the potential to prolong survival in SCLC patients. In fact, atezolizumab when combined with chemotherapy has achieved the milestone of being the first drug to improve survival in patients with newly diagnosed extensive-stage SCLC. Other immunotherapeutic approaches evaluated in clinical trials for SCLC include the use of cytokines, cancer vaccines, antiganglioside therapies, TLR9 inhibition, anti-Notch signaling, and anti-CD47. This review discusses the rationale and clinical evidence of immunotherapy in SCLC, the conflictive clinical results of novel immunotherapeutic agents and combinatorial therapies under evaluation in SCLC patients.

The role of immunotherapy in small cell lung cancer.

P1.15-004 An Open-Label, Multitumor Phase II Basket Study of Olaparib and Durvalumab (MEDIOLA): Results in Patients with Relapsed SCLC

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P1.15-004 An Open-Label, Multitumor Phase II Basket Study of Olaparib and Durvalumab (MEDIOLA): Results in Patients with Relapsed SCLC