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Multidisciplinary Immuno-Oncology Symposium: Samra Turajlic

Escape from nonsense mediated decay associates with anti-tumor immunogenicity

Frameshift insertion/deletions (fs-indels) are an infrequent but potentially highly immunogenic mutation subtype. Although fs-indel transcripts are susceptible to degradation through the non-sense mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and lead to an increased abundance of tumor specific neoantigens, that are highly distinct from self. We analysed matched DNA and RNA sequencing data from TCGA, and four separate melanoma cohorts treated with immunotherapy. Using allele-specific expression analysis we show that expressed fs-indels were enriched in genomic positions predicted to escape NMD, and associated with higher protein expression, consistent with degradation escape (“NMD-escape”). Given the strongly immunogenic potential, and relatively rare nature of NMD-escape fs-indels, these alterations may be attractive candidates in immunotherapy biomarker optimisation and neoantigen ACT or vaccine strategies.

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Congress news 15/10/2018

Multidisciplinary Immuno-Oncology Symposium: Lorenza_Landi

Immumotherapy in first line treatment of NSCLC? During the last decade, improvements in cancer biology and immune system knowledge led to a significant prolongation in overall survival for patients with metastatic non-small cell lung cancer (NSCLC). It is well established that immune system plays a critical role in destroying cancer cells. Tumor cells, however, use different strategies to avoid recognition by the immune system, including “immune checkpoint” activation. Programmed death-1 (PD-1) immune checkpoint pathways have been the one most extensively studied. Several agents interfering with the PD-1 axes have been evaluated in clinical trials. Since these drugs directly target the patient’s immune system, they have the potential for utility across multiple tumor types, including lung cancer. The PD-1 receptor is expressed on activated T-cells, and the key ligands for this receptor are programmed death-ligands 1 (PD-L1) and 2 (PD-L2). PD-L1 is up-regulated in many tumors and high levels of expression (³50%) have been observed in approximately 30% of NSCLC. This overexpression helps tumor to evade immune responses. Binding of PD-L1 or PD-L2 to PD-1 receptors inhibits T-cell activation reducing antitumor immune responses. Therefore, PD-1 represents a logical target for cancer immunotherapy. At the present time, in first-line setting, immunotherapy as single agent or in combination with chemotherapy is the standard of care in PD-L1 expressing patients, target therapy is recommended in oncogene addicted and the proportion of patients still candidate for exclusive chemotherapy is gradually decreasing. Agents targeting PD-1 or PD-L1, such as pembrolizumab, nivolumab or atezolizumab, are now approved in clinical practice in first or in second-line setting. Results from several randomized clinical trials comparing immunotherapy as single agent or in combination with chemotherapy versus chemotherapy alone are rising the question on what is the best first-line treatment and whether platinum-based chemotherapy could be avoided in our patients. Three phase III studies compared immunotherapy as single agent versus platinum-based chemotherapy. The Keynote 024 study compared pembrolizumab monotherapy versus platinum-based doublets in NSCLC patients with high PD-L1 expression. The study demonstrated that pembrolizumab is superior to chemotherapy by doubling median overall survival (OS: 30.0 versus 14.2 months, p=0.002). Similar results were obtained in the Keynote 042 trial, a phase III study comparing pembrolizumab versus  chemotherapy in patients with at least 1% of PD-L1 expression. This study, including a large percentage of patients with PD-L1 expression ≥ 50%, confirmed the superiority of pembrolizumab versus chemotherapy in terms of OS (20.0 versus 12.2 months, p=0.003). In contrast, the Checkmate 026 study, comparing nivolumab versus chemotherapy in patients with at least 1% of PD-L1 expression, showed no OS difference in both arms even in the subgroup of patients with PD-L1 expression ≥ 50%. Importantly, both Keynote 042 and Checkmate 026 showed no survival improvement in patients with low levels of PD-L1 expression (1-49%). Four different phase III trials, two in non-squamous (Keynote 189 and IMPOWER 150) and two in squamous histology (Keynote 407 and IMPOWER 131), compared standard chemotherapy plus a checkpoint inhibitor versus chemotherapy alone. The Keynote 189, evaluating pembrolizumab plus chemotherapy versus chemotherapy alone, showed a significant improvement in OS when pembrolizumab was added to chemotherapy in all patient subgroups, irrespective of PD-L1 expression. Interestingly, the OS Hazard Ratio (HR) was better than the HR obtained in studies with pembrolizumab monotherapy, suggesting that combination of immunotherapy and chemotherapy could be superior to chemotherapy alone even in patients with high levels of PD-L1 expression, with the cost of increased toxicity. The IMPOWER 150, a large 3 arms study (atezolizumab plus carboplatin-paclitaxel: Arm A; or atezolizumab  carboplatin-paclitaxel-bevacizumab: Arm B; or carboplatin-paclitaxel-bevacizumab: Arm C), demonstrated a significant survival improvement for arm B versus C but not in arm A versus arm C, at least in at the initial survival analysis. The Keynote 407 compared pembrolizumab plus carboplatin-taxol (paclitaxel or nab-paclitaxel) versus the same chemotherapy regimens in patients with squamous histology. Similarly to Keynote 189, addition of pembrolizumab to chemotherapy yielded in a OS improvement in patients receiving immunotherapy, irrespective of PD-L1 expression. The IMPOWER 131 was a 3 arms study comparing atezolizumab plus carboplatin-paclitaxel (Arm A) or atezolizumab plus carboplatin-nab-paclitaxel (Arm B) versus carboplatin-nab-paclitaxel as initial therapy in patients with squamous histology. Although arm B was superior to arm C in terms of progression-free-survival (PFS), the first interim analysis showed that OS improvement was confined to individuals with PD-L1 expression ≥ 50%. Finally, of particular interest are the  preliminary data from the PD-L1 negative cohort included in the Checkmate 227 study. In this trial, PD-L1 negative patients were randomized to nivolumab plus ipilimumab versus platinum-based chemotherapy versus platinum-based chemotherapy plus nivolumab. In patients with high Tumor Mutational Burden (high-TMB), defined as patients with ≥ 10 mutations/Mb, PFS at 12 months was almost 5 times higher with nivolumab-ipilimumab and 3 times higher with chemotherapy plus nivolumab than in individuals treated with chemotherapy alone. In patients with low TMB no difference in PFS was observed in the three arms. Overall these data support TMB and a relevant biomarker for refining selection of patients candidate to immunotherapy. Overall, all available data demonstrated that immunotherapy is the new standard of care as initial therapy in patients with NSCLC irrespective of histology. Current evidence support usage of immunotherapy single agent only in PD-L1 ≥ 50%. For patients with low or no PD-L1 expression immunotherapy plus chemotherapy is superior to chemotherapy alone. Combination of PD-L1 expression and TMB could better define in which patients chemotherapy can be avoided and in which patients immunotherapy is not effective.

Congress news 15/10/2018

Multidisciplinary Immuno-Oncology Symposium: Bart Neyns

Melanoma: when to stop immuno therapy? Blockade of the programmed cell death protein 1 (PD-1, CD279) cell surface receptor relicenses anti-tumor T-cell activity in a tumor micro-environment with expression of the programmed death-ligand 1(PD-L1; CD274) on tumor- and/or other tumor infiltrating cells. The PD-1 blocking monoclonal antibodies (mAb) pembrolizumab and nivolumab demonstrated an overall survival (OS) benefit when compared to ipilimumab or dacarbazine as first line therapy in patients with advanced melanoma.1-3Objective responses were observed in 27-40% of advanced melanoma patients and found to be durable in the majority of patients.1,4 One- and 2-year survival rates were in the order of 57% to 70%. Follow-up of patients treated on a phase I clinical trial with nivolumab revealed that anti-tumor responses were ongoing after the cessation of PD-1 therapy; 12 (71%) of 17 patients who stopped therapy for reasons other than PD maintained their responses for at least 16 weeks off-treatment.5 Similarly, in the phase I KEYNOTE-001 trial, the 24-month disease-free survival (DFS) from time of complete tumor response (CR) was 89.9% in the subgroup of 67 patients who stopped pembrolizumab treatment after obtaining a CR (and who proceeded to observation without additional anticancer therapy).6 In the phase III KEYNOTE-006 trial, pembrolizumab was administered for a maximum duration of 24 months in patients with stable disease (SD), partial response (PR) and CR as best response. In the subgroup of 103 patients who stopped treatment after the 24 months interval, 14 patients (15%) developed PD after a median follow up of 20.3 mo (range, 0.03-24.8). Patients were at higher risk for progression during their second year off therapy and a higer proportion of patients who stopped PEMBRO with a best response of PR or SD were at higher risk as compared to patients who had a CR at the time of stopping PEMBRO.7 The estimated risk for progression or appeared to differ by best response to pembrolizumab. A complete metabolic tumor response on FDG-PET/CT at one year following initiation of anti-PD1 may have utility in addition to CT based response assessment in predicting long-term progression-free survival. 8 We previously reported on the outcome of advanced melanoma patients treated with PD-1 therapy outside of an interventional clinical trial.9 This academic real-world cohort study was extended investigating the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (n = 167) or nivolumab (n = 18) in the absence of PD or treatment-limiting toxicity at 14 medical centers across Europe and Australia demonstrating that advanced melanoma patients who electively discontinued anti-PD-1 therapy in the absence of TLT or PD had a low risk for early disease progression, seemingly regardless of the duration of treatment (manuscript currently under review).

Congress news 15/10/2018

Multidisciplinary Immuno-Oncology Symposium: Maria Themeli

How can we make CAR T cell therapy more effective and safer? Adoptive cellular immunotherapy with chimeric antigen receptor engineered T (CAR-T) cells is currently achieving impressive clinical results in patients with hematologic malignancies. CARs are prototypic synthetic receptors wherein the extracellular input is a cell surface antigen and the intracellular output a composite T cell activating signal providing functional and metabolic cues to determine T cell fate. CAR therapy relies on engineering of T lymphocytes in order to redirect them to kill tumor cells and is the first paradigm of successful clinical use of cellular engineering with synthetic receptors.  When targeting CD19, a cell surface molecule found in most leukemias and lymphomas, CAR T cells have produced remarkable clinical results, validating the synthetic biology approach to cancer immunotherapy and consecutively the potential for application to other hematological malignancies and solid tumors. To attain broader relevance, T cell engineering and CAR therapy in particular must achieve effective tumor targeting and tumor elimination with minimal or tolerable toxicity. While therapeutic efficacy of CAR-T cell therapy has been remarkable, a critical mechanism of disease escape includes lack of uniform expression of the target antigen within the clonal tumor populations or downregulation of antigen expression to evade effector cell mediated killing.  CD19 CAR-T cell therapy often fails owing to CD19-negative relapse and first clinical trials of BCMA-CAR-T cells have already reported relapses of BCMA negative/low clonal variants. In addition, persistence of CAR-T cells has been inconsistent with some studies demonstrating a correlation between early extinguishing of the CAR-T cell population and the development of resistance.  As such, strategies to broaden CAR-T cell mediated targeting of the tumor population and enhance their activation, expansion and durability is critical to develop this potential paradigm changing therapy. The broader applicability of CAR therapy is also impeded by safety concerns regarding the on-target/off-tumor effect of CAR T cells on normal tissues due to the lack of unique tumor-specific surface targets. Although the B-cell aplasia caused by CD19-CAR T cells is an easily manageable clinical situation, this is likely not the case for the majority of potential CAR targets. In addition, the experience of CD19-CAR T cell clinical trials brought into attention the cytokine release syndrome (CRS), mediated by large numbers of tumor-targeted activated T cells, as another safety issue of CAR therapy. Several strategies have already been proposed to regulate CAR T cell function. These include the use of suicide gene strategies, such as the inducible caspase-9 (iCasp9) enzyme, to terminate T cell activity, bispecific small molecules that transiently bridge antigen and CAR T cells, οr dimerizing agents that transiently link the antigen-binding and signaling domains of a CAR. The above studies allow remote temporal control of CAR T cell activity, but they do not address spatial control of antigen engagement and tumor selectivity. To the latter end, affinity tuning or engaging two antigens rather than one provide an interesting paradigm for achieving greater tumor selectivity.

Congress news 11/12/2019

SMR 2019: Pier Ferrucci

There are a couple of ongoing trials examining the combination of immunotherapy and targeted therapy. One of them is the KEYNOTE-022 trial. Dr. Pier Francesco Ferrucci comments on the efficacy and toxicity of the combination of pembrolizumab, dabrafenib and trametinib in comparison to dabrafenib, trametinib and placebo.

Congress news 11/12/2019

SMR 2019: Grant McArthur

It was already clear that the BRAF/MEK-combination cobimetinib + vemurafenib performs better then vemurafenib + placebo in terms of efficacy. On the SMR 2019 five-year survival results were presented. Prof. Grant McArthur talks you through the efficacy and toxicity and discusses the significance of these new data on daily clinical practice.

Congress news 11/12/2019

SMR 2019: Nethanel Asher

It is always interesting and insightful to see how results of clinical trials translate to daily clinical practice. Dr. Nethanel Asher runs you through the real world outcomes of the combination of ipilimumab and nivolumab in patients with advanced melanoma.

Congress news 11/12/2019

SMR 2019: Top 3 highlights

On the SMR 2019 an innumerable ammount of data, both clinical and preclinical, has been presented. Prof. Sean Morrison gives his personal highlights of this congress.