| | | | | Selection of TP53 missing mutation driven by a dominant-negative effect Despite being the most frequently mutated gene in human cancer, TP53, the gene encoding p53, has a mutational spectrum that is still not completely elucidated. Boettcher et al. Used novel CRISPR — Cas9, DNA binding and transcriptional analysis, and comprehensive mutational scanning techniques to study the most common TP53 missing mutations in human leukemia. Results revealed a dominant-negative effect exerted by missing variants in the DNA binding domain or p53. In mouse models, this reduces the tumor suppressor activity or wild-type p53. In conclusion, the selection of TP53 missing mutations is driven by a loss-of-function rather than a neomorphic gain-of-function effect, as previously speculated in the field. Results were published inScience (Image source: Boettcher et al., Science ). |
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| Neutral genetic drift as cause or long-term cancer evolution The canine transmissible venereal tumor (CTVT) is a cancer lineage first developed several millennia ago and presenting with somatic mutations that record its phylogeography and evolutionary history. Analyzing 546 different CTVT exomes, Baez-Ortega et al. constructed a time-resolved phylogeny and described the lineage's worldwide expansion. Computational methods helped identify a context-specific mutational process that operated early in the cancer's evolution but disappeared. Furthermore, the authors highlighted the correlation between ultraviolet-light mutagenesis and tumor latitude. Lastly, negative selection was detected only in essential genes. This, together with the lack of evidence or positive selection, reveal that the dominant feature of long-term cancer evolution is neutral genetic drift. Results were presented in Science (Image source: Baez-Ortega et al, Science ). |
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| Infusions of humanized anti-CD19 and anti-BCMA CAR T cells are feasible The limited efficacy of chimeric antigen receptor (CAR) T-cell therapy in myeloma observed in the past due to targeting or infusion-related issues has prompted researchers to develop new CAR T-cell types. In a recent study, Yan et al. assessed safety and efficacy of the new combination of humanized anti-CD19 and anti-B-cell maturation antigen (BCMA) CAR T-cells in patients with relapsed / refractory multiple myeloma. At a median follow-up of 179 days, 43% of patients had stringent complete response (CR), 14% had CR, 24% had very good partial response (PR), and 14% had PR, thus leading to an overall response in 95% of patients in this frail population. While serious adverse events were observed in 95% of patients, with one patient dying due to cerebral hemorrhage, this was not judged to be treatment-related. These results confirm that combined infusion of humanized anti-CD19 and anti-BCMA CAR T-cells is feasible and might be a promising treatment option for patients with relapsed / refractory disease. Results were published in The Lancet Haematology. |
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Industry Aquinox Pharmaceuticals and the privately held Neoleukin Therapeutics announce merger agreement. The combined company will focus on the development of computationally-designed protein therapeutics for use in immuno-oncology. Neoleukin's lead product candidate, NL-201, is a de novo protein designed to mimic the therapeutic activity of interleukin-2 and interleukin-15 for treatment of various cancers by activating both T-cells and NK cells. Global pharma Bayer buys out Blue Rock Therapeutics, a privately held US biotechnology company. By agreeing to pay $ 240m, Bayer will own full rights to BlueRock's CELL + GENE platform and its proprietary induced pluripotent voice cell (iPSC) technology, currently under development as a cheaper and easier-to-produce alternative to the autologous chimeric antigen receptor ( CAR) T-cell cancer therapy. Former executive Levi Garraway as CMO of Roche: The international pharmaceutical company Roche appointed Levi Garraway, former Eli Lilly's senior vice president for the oncology division, to succeed Sandra Horning as CMO and head of global product development at Roche. This has significant relevance for Levi Garraway, who co-founded in 2010 Foundation Medicine, a company providing tumor molecular information. |
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| EMA / FDA The Committee for Medical Products for Human Use (CHMP) had no meeting in August. Britain's drug, devices, and pricing regulators leave in anticipation or Brexit: The Medicines and Healthcare products Regulatory Agency (MHRA) is officially UK's drug regulator. While most of the decisions regarding new drugs coming into the UK were duties by the European Medicines Agency (EMA), this will now be turned over to MHRA as a result of the impending Brexit. Despite the fact that UK is, for the near future, set to follow EMA's drug rules, the chief executive of MHRA, dr. Ian Hudson, and its director of devices, Dr. John Wilkinson, have recently announced their departure and, respectively, retirement. It is not yet clear whether Hudson would remain in regulation or would move externally, to the life sciences industry. What is however clear is that Sir Andrew Dillon, chief executive of the National Institute for Health and Care Excellence for its entire two-decade life, also announced his upcoming departure from England’s drug pricing watchdog. FDA The FDA granted approval for: Inrebic (fedratinib, Celgene), for treatment of patients with intermediate-2 or high-risk primary or secondary myelofibrosis. The approval was based on the JAKARTA trial, whose results reported a ≥35% reduction from baseline to the end of cycle 6 in spleen volumes of patients receiving fedratinib as compared with placebo. This is the first new treatment approved for primary or secondary myelofibrosis in nearly a decade. Rozlytrek (entrectinib, Roche), for treatment of reactive oxygen species (ROS) 1-positive, metastatic non-small cell lung cancer and neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive solid tumors. This is the first FDA-approved treatment designed to target both ROS and NTRK that also shows response in cancer that has spread to the brain. Turalio (pexidartinib, Daiichi-Sankyo), for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. TGCT is a rare, non-malignant tumor that affects small and large joints, and pexidartinib is the first and only treatment approved by the FDA for this disease. Nubeqa (darolutamide, Bayer), an androgen receptor inhibitor, for treatment of patients with non-metastatic castration-resistant prostate cancer. The FDA approval was based on the phase III ARAMIS trial results, which demonstrated a significant improvement in metastasis-free survival (median MFS; darolutamide plus androgen deprivation therapy [ADT] vs placebo plus ADT: 40.4 vs 18.4 months) Keytruda (pembrolizumab, Merck), an anti-PD-1 antibody, for treatment of patients with recurrent locally advanced/metastatic esophagus squamous cell carcinomas (ESCC) that express PD-L1 (Combined Positive Score [CPS] ≥10, as determined by the FDA-approved test PD-L1 IHC 22C3 pharmDx), with disease progression after one or more prior lines of systemic therapy. This is a new monotherapy indication for pembrolizumab, which is already approved for first-line treatment of patients with metastatic/unresectable recurrent head and neck squamous cell carcinoma. PD-L1 IHC 22C3 pharmDx (Agilent Biotechnologies Inc.), an assay that precisely identifies patients with ESCC for subsequent treatment with pembrolizumab. The assay is the only FDA-approved companion diagnostic to aid in identifying ESCC patients for second-line treatment with pembrolizumab. In addition to approvals, FDA granted breakthrough therapy designation to several products to progress their development. These include: Bempegaldesleukin (NKTR-214), in combination with Opdivo (nivolumab), for the treatment of patients with untreated advanced melanoma. The designation was granted based on the PIVOT-02 phase II trial, whose results reported a 34% rate of complete response at the 12-month follow-up and a complete reduction in target lesions in 42% of patients treated with the combination therapy. Calquence (acalabrutinib), as monotherapy for patients with chronic lymphocytic leukemia (CLL). The designation was granted based on the ELEVATE-TN and ASCEND phase III trials, which reported a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in the acalabrutinib and obinutuxumab versus the chlorambucil and obinutuzumab treatment arms. In addition to approvals in the US and EU, approvals were also granted in Japan for: Darzalex (daratumumab, Genmab), in combination with bortezomib, melphalan, and prednisone for the treatment of patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplantation. The approval was based on results from the ALCYONE phase III trial that showed a 50% reduction of the risk of disease progression or death upon combined treatment including daratumumab. |
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