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Enjoy reading! - The SMS-oncology team
Tumor-associated reactive astrocytes play a role in immunosuppression
In Glioblastoma Multiforme (GBM), the role of reactive astrocytes and their crosstalk to the environment is poorly understood. Based on RNA-seq gene expression analysis of these cells, Heiland et al. found that tumor-associated reactive astrocytes had a distinct transcriptional phenotype compared to normal astrocytes, with an increased expression of immune-associated genes (e.g. CHI3L1, HLA-DRA, PD-L1, HLA-DRB3, and CD37). This phenotype was responsible for the large release of anti-inflammatory cytokines (e.g. TGFβ, IL10, and G-CSF) and linked to JAK/STAT pathway activation. Assessment of the top 50 signature genes revealed a multidimensional shift towards a progenitor and alternative activation state, driven by tumor and microglia cells, and promoted by the cytokine environment. The complex interaction between astrocytes and the microglia promotes an immune-suppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.
(Image source: Heiland et al., Nature Communications)
Prognostic value of tumor-infiltrating CD8+ T cells is related to spatial distribution
The density of cytotoxic tumor infiltrating lymphocytes (TILs) within the tumor and its microenvironment plays a crucial role in patient outcome. A recent study performed by Masugi et al., the distribution of CD8+ TILs was evaluated by multiplex immunohistochemistry-based image analysis in whole-tissue samples from 214 patients with pancreatic ductal adenocarcinomas. A multivariate Cox regression analysis revealed a significant association between higher CD8+ TIL density in the tumor margin, but not the tumor center, and tumor PD-L1 expression. The study revealed for the first time the prognostic validity of CD8+ TIL density in the tumor center and marks the first steps in potentially using state-of-the-art spatial computational analysis for improving the therapeutic design for cancer patients.
Somatic clonal expansion across normal tissues
Cancer genome studies have contributed to the discovery of mutations driving cancer development, however to date has been limited to already established tumors instead of analyzing somatic mutations accumulating in normal tissues prior to cancer formation. Yizhak et al. performed the first broad characterization of macroscopic clonal expansion across a large number of tissues and individuals made use of a novel method detecting mutations from RNA sequencing (RNA-MuTect) to assess tissue-specific mutation accumulation in Cancer Genome Atlas (CGA) samples and normal samples from the Genotype-Tissue Expression (GTEx) project. RNA sequences from more than 6700 samples (488 individuals, 29 different normal tissues) revealed the presence of multiple somatic mutations, including in known cancer genes, in almost all individuals studied. The highest numbers of somatic mutations were found in sun-exposed skin, esophagus mucosa, and lung, which can be explained by a higher cell turnover due to exposure to the sun or other pollutants (associated with tissue-specific proliferation rate and age).
(Image source: Yizhak et al., Science)
Pfizer to acquire Array Biopharma: The American multinational pharmaceutical corporation Pfizer has entered into a definitive merger agreement to acquire Array BioPharma Inc., a biopharmaceutical company focused on discovery, development and commercialization of targeted small molecule drug to treat cancer. Pfizer will acquire Array for $48 per share for a total enterprise value of approximately $11.4B. As Array's drug portfolio includes the approved combined use of BRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) for treatment of BRAFV600E/BRAFV600K mutant unresectable/metastatic melanoma, the proposed acquisition will strengthen Pfizer’s innovative business and aims to accelerate its long-term growth trajectory.
Merck to acquire Tilos Therapeutics: Pharmaceutical giant Merck has entered into a definitive agreement to acquire the privately held biopharmaceutical company Tilos Therapeutics. Through a subsidiary, Merck will acquire all outstanding shares of Tilos for total potential consideration of up to $773M; including an upfront payment as well as contingent milestone payments. Tilos Therapeutics develops novel antibodies targeting the latent TGFβ complex for the treatment of cancer, fibrosis, and autoimmune diseases. This work is of high relevance for Merck, which is looking into different ways to broaden the reach of its blockbuster cancer immunotherapy pembrolizumab (Keytruda).
EMA / FDA
The Committee for Medical Products for Human Use (CHMP) adopted a positive opinion for:
- Azacitidine (azacitidine, Celgene) for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukemia. The pyrimidine analogue exerts its antineoplastic effects by cytotoxicity on cells in the bone marrow and hypomethylation of DNA.
The CHMP gave positive recommendation on extensions of indications for:
- Cyramza (ramucirumab, Eli Lilly) for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma who have a serum alpha fetoprotein (AFP) of ≥ 400 ng/ml and who have been previously treated with sorafenib. The monoclonal antibody was already approved for specific forms of gastric cancer, colorectal cancer and non-small cell lung cancer.
- Imbruvica (ibrutinib, Janssen-Cilag International) in combination with obinutuzumab for the treatment of untreated chronic lymphocytic leukemia, and in combination with rituximab for the treatment of adult patients with Waldenström’s macroglobulinaemia.
- Tecentriq (atezolizumab, Roche) in combination with nab-paclitaxel for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumours have PD-L1 expression ≥ 1% and who have not received prior chemotherapy for metastatic disease. The monoclonal antibody was already approved for other cancers such as NSCLC and urothelial carcinoma.
The FDA granted approval for:
- Darzalex (daratumumab, Janssen Biotech) in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. The IgG1k monoclonal antibody directed against CD38, a glycoprotein highly expressed in multiple myeloma cells, as well used as a prognostic marker in leukemia.
- Keytruda (pembrolizumab, Merck) as first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC), in combination with platinum and fluorouracil for all patients and as a single agent for patients with PD-L1-expressing tumors (combined positive score [CPS] ≥1) as determined by an FDA-approved test.
Keytruda was also approved for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).
- Polivy (polatuzumab vedotin-piiq, Genentech) a novel antibody-drug conjugate in combination with the chemotherapy bendamustine and a rituximab product (BR) as the first chemo-immunotherapy regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The accelerated approval was granted based on the results of a phase I/IIb clinical trial demonstrating that patients randomized to the combination of polatuzumab vedotin piiq-BR showed an improved complete response rate versus those receiving only BR (40% vs 18%).
- Kanjinti (trastuzumab-anns, Amgen and Allergan's biosimilar to Herceptin®) for all approved indications of the reference product, namely the treatment of HER2-overexpressing adjuvant and metastatic breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. KANJINTI demonstrates similar safety and immunogenicity in patients who were being previously treated with the reference product and is currently the only trastuzumab biosimilar that incorporates the evaluation of a single transition in the clinical study.
Critical assessment of eligibility criteria can double patient recruitment rates
As many as 80% of the clinical trials are delayed due to recruitment issues. At this year’s ASCO, it was shown that eligibility criteria that are set too strict are a major factor hindering patient accrual onto clinical trials. A retrospective analysis of deidentified electronic health record data from 10,500 patients with non-small cell lung cancer investigated the impact of traditional eligibility criteria versus more relaxed criteria on enrollment. In most studies, patients with brain metastases, a history of prior malignancy and/or impaired renal function are excluded. Applying the more relaxed criteria that have been proposed by ASCO and Friends of Cancer Research instead of traditional criteria resulted in improved eligibility from 52.3% to 98.5% of the patients. This analysis shows that using eligibility criteria as a template from one protocol to the other may hinder clinical research and that critical appraisal of the eligibility criteria per study protocol is of great importance.