Oncology Highlights - February 2018
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Enjoy reading! - The SMS-oncology team
Since the approval of the first immunotherapy (interferon-α) in 1986, there has been a rapid progress in the IO field over the last 30 years; followed by further 25 agents, 17 types of cancer now have at least one agent approved as a treatment option. However together with the huge investment from industry and a plethora of companies entering the field, there is now an unprecedented number of new immunotherapy agents at various stages in the drug development pipeline which makes it overwhelming to keep track of what’s going on. A recent paper published in Annals of Oncology aims to curate a comprehensive overview of the IO landscape. Authors of the paper from Anna-Maria Kellen Clinical Accelerator of the Cancer Research Institute (CRI) developed two databases: a total number of 2,004 immuno-oncology agents (940 in clinical stage and 1,064 in pre-clinical testing) and a total of 3,042 active clinical trials – covering all common cancer types and the majority of the less common ones. One observation they made based on their datasets, is the large number of overlaps, with companies chasing the same targets. Another finding is the increase in the number of studies involving anti-PD-1/L1 combinations, many of which are testing the same combinations. The most two common of PD-1/L1 combination trials are with Pembrolizumab (399 trials) and Nivolumab (340 trials). The data also indicates the growing number of small studies, initiated by investigators. The team aims to work with the clinical community to build an unbiased, neutral comprehensive information hub for IO to keep-up with the trends, to avoid overlaps and in efficiencies. All the resources used for the database is publicly available on the CRI website and will be updated on a quarterly basis.
Induced pluripotent stem cells, or IPSCs, are a keystone of regenerative medicine. Now, a study in mice from the Stanford University School of Medicine suggests another use for IPSCs: training the immune system to attack or even prevent tumors. The idea stems from the similarities between cancer and IPSCs. They are very much alike in their resemblance to developmentally immature progenitor cells, which are free from the growth restrictions built into mature cells that make up the body’s tissues. Looking closer, researchers found some remarkable similarities in the gene expression panels of the two types of cells in mice and humans, suggesting that these cells share proteins on their surfaces called epitopes that could serve as targets for the immune system. The study showed that injecting mice with genetically matching IPSCs (irradiated to prevent the formation of teratomas) in combination with an adjuvant generic immune-stimulating agent, prevented the growth of breast cancer xenografts transplanted in this animals even after a year. The results indicate that the immune system could be primed to reject the development of tumors after the “vaccination” with IPSCs. Pending replication in humans, their findings indicate these cells may one day serve as a true patient-specific cancer vaccine. Study was published online in Cell Stem Cell.
Can DNA sheets be folded in a specific shape to form a package to deliver drugs specifically in to tumor tissue? The answer is yes and they are called DNA nanorobots. In a recent paper published in Nature Biotechnology the team have demonstrated that it’s indeed possible to do site-specific drug delivery using biocompatible, biodegradable, DNA-based bionanorobots for cancer therapeutics. Researchers first generated a self-assembling, rectangular, DNA-origami sheet to which they linked thrombin, an enzyme responsible for blood clotting. Then, they used DNA fasteners to join the long edges of the rectangle, resulting in a tubular nanorobot with thrombin on the inside. The authors designed the fasteners to dissociate when they bind nucleolin—a protein specific to the surface of tumor blood-vessel cells—at which point, the tube opens and exposes its cargo. These nano-robots were injected in mice with breast cancer transplant and demonstrated to form extensive blood clots in the tumors’ vessels within 48 hours, but did not cause clotting elsewhere in the animals’ bodies. These blood clots led to tumor-cell necrosis, resulting in smaller tumors and a better chance for survival compared to control mice.
Immuno-oncology combination frenzy: Record breaking pact from Bristol-Myers Squibb for Nektar cancer drug, and Merck deal with Viralytics
IO combination therapy on cancer just got even hotter! Bristol-Myers Squibb announced to pay a record $1.85 billion to Nektar Therapeutics, a small biotech startup, for rights to its experimental cancer drug, NKTR-214. NKTR-214 is a CD122-biased agonist designed treat solid tumors through stimulating Tumor Infiltrating Cells (TILs) and Natural Killing cells (NKs). Nektar will book 65% of global profits on the drug, should it reach the market, with Bristol getting the other 35%. This deal is one of, if not the, biggest up-front partnership fees involving a single development stage biotech in biotech history. The lion’s share marriage gives the exclusive rights for IO-combi therapy: NKTR-214 in combinations with Opdivo and Yervoy, for 20 different uses in 9 cancer types (think lung cancer, melanoma, or kidney cancer). In a similar partnership, Merck agreed to pay $394 million for Viralytics, an Australian developer of oncolytic viruses, which could help boost the power of the pembrolizumab (Keytruda). IO-IO combinations are expected to get hotter in 2018 as a solution to inefficiencies of the mono-IO therapy.
The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for:
Gemtuzumab ozogamicin (Mylotarg, Pfizer) for the treatment of acute myeloid leukaemia in patients aged 15 years and above. Gemtuzumab ozogamicin (humanised IgG4 antibody) is an anti-CD33 which is conjugated to calicheamicin, a toxin that induces cell cycle arrest and apoptotic cell death.
The FDA granted regular approval for:
- Abemaciclib (Verzenio, Eli Lilly) for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women. The CDK4-CDK6 inhibitor was designated as a breakthrough therapy for breast cancer by the FDA in 2015.
- Durvalumab (Imfinzi, AstraZeneca Pharmaceuticals) for the treatment of patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. The PD-L1 inhibitor is the third most commonly used agent in IO-IO combination therapies in clinical trials at the moment (following Pembrolizumab and Nivolumab as mentioned in the first alinea above)
- Apalutamide (Erleada, Janssen Biotech) for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (CRPC). Approval was based on SPARTAN trial involving randomized 1,207 patients.
Abiraterone acetate (Zytiga, Janssen Biotech) for the treatment of adult patients with metastatic high-risk castration-sensitive prostate cancer (CSPC) in combination with prednisone. Zytiga has been earlier approved for CRPC with prednisone in 2011, and as a monotherapy in 2012. The CYP17 inhibitor (and by extension androgen synthesis inhibitor) was indicated in the top 10 oncology products of 2017 based on revenue.
Bolstering the immune system’s response, side effects associated with immune checkpoint inhibitors can involve multiple organs, and can be severe and irreversible. Increasingly wide-spread however immune checkpoint inhibitors is relatively recent, doctors are not necessarily highly experienced in recognizing and treating such side effects. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recently developed a set of guidelines to serve as recommendations to clinicians regarding how to assess and manage the side effects associated with immune checkpoint inhibitors. The guidelines recommend for mild toxicities (grade 1) — except for some neurologic and hematologic toxicities — to continue with treatment; for moderate toxicities (grade 2), temporarily stop use of checkpoint inhibitors until lab work or symptoms show the reaction is mild or better; corticosteroids can be a replacement therapy. If the cancer patient shows severe toxicity (grade 3), this can be managed with high-dose corticosteroids for at least six weeks; extreme caution is advised when restarting immunotherapy; with evidence of very severe cases of toxicity (grade 4), immediately and permanently stop use the checkpoint inhibitor. The results were published in the Journal of Clinical Oncology.