Oncology Highlights - October 2018
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Enjoy reading! - The SMS-oncology team
Cyclin-dependent kinases (CDKs) are hot targets in cancer research. Moving from pan-CDK inhibitors to selective CDK inhibitors, researchers have been aiming to target specific CDKs to dismantle their anti-tumor effects due to their functions in DNA replication and cell cycle progression. In a recent study published in Cell, researchers at Lewis Katz School of Medicine at Temple University show that inhibiting CDK9, a transcription regulator, reactivates genes that have been epigenetically silenced by cancer. Reactivation leads to restored tumor suppressor gene expression and enhanced anti-cancer immunity. This is the first time a particular kinase has been linked to gene silencing in mammals. Furthermore, CDK9 inhibition was found to induce sensitivity to the immune PD1 checkpoint inhibitor in vivo, paving the way for combination studies.
Although immune checkpoint inhibitors (ICIs) lead to durable responses in patients with metastatic melanoma, refractory disease and progression after initial response remain major causes of mortality. Now, a team led by researchers from Broad Institute of MIT, Harvard and Dana-Farber Cancer Institute has identified a gene expression pattern that human melanoma cells use to resist immunotherapy, and demonstrated a combination therapy approach that could overcome this resistance. In this study published in Cell, they used single-cell RNA sequencing (scRNAseq) to determine cell specific markers from tumor biopsies of patients treated with checkpoint therapy. Using biopsies from 32 patients either at baseline or after ICI treatment, they profiled the CD8+ T Cells in responders and non-responders. They found that elevated levels of TCF7 cell surface protein predicts the positive outcome for the treatment. In contrast to TCF7+, CD39 expressing cells were associated with a lack of response to ICI therapy. Results suggests that analysis of patient’s different T cell gene expression states will help designing better fit treatments.
Transforming growth factor-Beta (TGFβ) is a comprehensively studied cytokine involved in tumorigenesis, produced by Tregs (regulatory T lymphocytes) to induce immunosuppression. TGFβ and its downstream signaling pathway are therefore popular targets for cancer treatment. However, TGFβ is complex and finely regulated and the mechanism of TGFβ activation has been unclear and difficult to target. In a study published in Science, Belgian research groups elucidated the three-dimensional structure TGFβ activation assembly and developed a specific antibody that can block this assembly to inhibit the immunosuppression it induces downstream. TGFβ is released in a latent form by GARP cell surface protein on Tregs and subsequently activated which has been difficult to visualize due to instability. In a collaboration with scientists from UC Louvain and WELBIO, VIB and Ghent University, and the biotech company argenx, stabilizing antibody was developed permiting X-ray crystallography visualization and revealing the structure of GARP TGFβ complex. The antibody targets GARP TGFβ assembly gluing two molecules to one another. This can be used as an alternative method to inhibit TGFβ, ensuring it is not released, and is thus prevented from conveying its inhibitory message.
October was a busy month in terms of oncology M&A deals or partnerships: Mymetics, a Swiss virosome based vaccine developer with a research lab in the Netherlands, and the Belgian company eTheRNA agreed to combine virosome vaccine delivery technology with eTheRNA's proprietary TriMix mRNA. In another collaboration, shRNA platform to power up CAR-T cell therapies through the partnership of Celyad and Horizon Discovery. Leveraging Horizon’s shRNA platform, Celyad plans to develop allogeneic CAR-T cells. Also, GO Therapeutics has entered into a license agreement with Roche that will grant French drugmaker to develop a novel cancer specific target and commercialize a new glycotargeting bispecific antibody. Roche will pay GO upfront and near-term milestones of $9M. Kite and HiFiBiO handshake to combine powers in cell based therapeutics. Adopting HiFiBiO’ s single cell technology platform, the collaboration will support discovery of neoantigen-reactive T cell receptors (TCRs). Kite will pay $10M upfront. Tango Therapeutics signed its first major business deal since debuting last year in a collaboration with Gilead. Tango’s robust target discovery platform uses CRISPR to identify vulnerabilities in specific types of cancer cells. Paying Cambridge biotech $50M, the duo will work to find new immunotherapy targets.
The Prix Galien was created in France in 1970 in honor of Galen, the father of medical science and modern pharmacology. Worldwide, the Prix Galien is regarded as the equivalent of the Nobel Prize in biopharmaceutical and medical technology research. In recognition of the development and discovery of products that improve the human condition, a committee of highly accomplished scientific leaders, inclusive of four Novel Laureates, recognized winners in three categories: "Best Pharmaceutical Product", "Best Biotechnology Product" and "Best Medical Technology". This year, innovative Hematology-oncology – especially immunotherapy marked the awards: the Committee has chosen Celgene-Agios’ IDHIFA for Best Pharmaceutical product. IDHIFA is an IDH2 inhibitor for patients with relapsed/refractory AML with an IDH mutation. For the Best Biotechnology product Novartis and Gilead's Kite shared the biotechnology award for CAR-T therapy. The 12th annual Prix Galien Awards Gala took place at New York’s Museum of Natural History.
The Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorization for:
- Ogivri (Trastuzumab, Mylan and Biocon), for the treatment of breast and gastric cancer. This biosimilar of the well-known mAb Herceptin for the treatment of HER2 positive cancers, representing 15% of breast cancers. Herceptin is among the top 3 selling oncology drugs worldwide. Europe’s first Herceptin biosimilar was Ontruzant which was approved by EMA in November 2017.
The CHMP extended the therapeutic indication for:
- Keytruda (Pembrolizumab, Merck) as monotherapy is indicated for the adjuvant treatment of melanoma in adults with lymph node involvement who have undergone complete resection.
The FDA granted regular approval for:
- Talzenna (Talazoparib, Pfizer) a poly (ADP-ribose) polymerase (PARP) inhibitor, for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2- locally advanced or metastatic breast cancer. Success of PARP blockers were highlighted in ESMO going beyond ovarian cancer, EMBRACA trial showed better patient-reported outcomes (PROs) compared to chemotherapy for triple-negative breast cancer (TNBC) patients.
- Keytruda (Pembrolizumab, Merck) in combination with carboplatin and either paclitaxel or nab-paclitaxel as first-line treatment of metastatic squamous non-small cell lung cancer. Approval was based on KEYNOTE-407 enrolling 559 patients with metastatic squamous NSCLC; regardless of PD-L1 tumor expression status, pembrolizumab 200 mg in combination with carboplatin significantly improved OS, PFS and ORR.
One draft guideline from FDA is published:
Hematologic malignancies: regulatory considerations for use of minimal residual disease in development of drug and biological products for treatment: This guidance is intended to assist sponsors planning to use minimal residual disease (MRD) as a biomarker in clinical trials varies across hematologic cancer types and patient populations. Persistence of malignancy can be detected via conventional morphologic assessments, at orders of magnitude below the morphologic detection, the level of disease burden is known as MRD. MRD can be genetic mutations or cell surface markers and may reflect a patient’s response to treatment or it may be used as a prognostic tool to assess the patient’s risk of future relapse. In this guideline FDA describes the considerations for the use of MRD with clinical validity. In order to avoid variability, sponsors should use standardized methodologies such as post-treatment timing for when a bone marrow (BM) or blood sample collected, standardized sample processing, predetermined MRD thresholds, and accurate reporting of the performance characteristics of the test (e.g., accuracy, precision, specificity, sensitivity).