Oncology Highlights - September 2016
Reading our newsletter will only take a few minutes and allows you to keep up to date with last month’s news items on oncology drug development.
Kind regards, the SMS-oncology team
Remote control (on/off switch) of CAR T cells to reduce side effects
The two most “hot” immuno-oncology therapies at the moment include checkpoint inhibitors and CAR T-cell therapy, of which the latter is currently only available in clinical trials. This therapy entails a customized approach wherein T cells are obtained from a patient, genetically modified to target a protein present on cancer cells (e.g. CD19 on cancerous B cells), and then given back. But these T cells are always switched on and non-selective for cancer cells, and consequently can deplete normal cells expressing the same protein (in lower levels) as well. Researchers have been looking for ways to control these infused cancer immunotherapy cells to keep a balance between the desired therapeutic effect and the side effects. A recent publication in the AACR’s journal Cancer Immunology Research shows that an engineered molecular “remote control switch” restricts the actions of T cells. The so-called Tet-on inducible system comprises of an on/off switch, the antibiotic doxycycline. When available, doxycycline can chemically link two modules of the engineered T cell receptor resulting in the activation of these CAR-T cells. When the administration of the antibiotic is stopped, the engineered T cells won’t be able to kill CD19 positive cancer cells; they are “off” by default. This mechanism may present a solution to the complications that have been a hurdle to advancing T cell-based treatments.
Cancer cells may spread by “lifting” on platelets via intergrin interaction
Metastases are the ultimate hallmark of malignancy and account for 90% of cancer mortality. Pierre Henri Mangin and colleagues at the Etablissement Français du Sang-Alsace have now reported in JCI Insight that a special molecule on platelets – termed α6β1 integrin – promotes spreading of cancer cells to other areas of the body. The team of researchers used a knockdown approach to find that α6β1 integrin supports platelet adhesion to various types of cancer cells by “lifting” on these cells. Mice lacking the molecule developed less metastasis in comparison, while blocking the integrin with an antibody stopped tumor spreading in certain tumor models. Additionally, α6β1 integrin was found to help tumor cells squeeze out of blood vessels. ADAM9 was identified as the major counter receptor of α6β1 on both human and mouse tumor cells. These discoveries suggest integrin α6β1 may be a promising target for anti-metastatic therapies.
New probable cancer treatment option: targeting four-stranded DNA helices
Researchers from the University of Cambridge in the UK show a promising new cancer treatment option in DNA molecules which have a four-stranded helix structure, also referred to as “G-quadruplexes” being often formed in DNA regions rich in the building block guanine (G). In 2013, the team already proved the existence of G-quadruplexes but were back then uncertain about their location and function. In the current publication in Nature Genetics, they suggest a key role of G-quadruplexes in controlling genes. The structures appeared to come and go, playing a role in switching genes on or off. The team could locate around 10,000 G-quadruplex regions, particularly prominent in genes associated with cancer. The accumulation of G-quadruplexes within pre-cancerous and cancerous cells indicates its effect on epigenetic marks and the researchers are excited about its potential as a target for early diagnosis and precision medicine.
Using magnetic bacteria for efficient drug delivery in tumors
Large percentage of anti-cancer drugs do not reach the tumor or are hindered to enter particularly the interior of it. This is unfortunate as the so-called “hypoxic zones” are believed to be the source of metastasis and targeting these low-oxygen regions will most likely decrease the rate of metastasis and maximize the beneficial effect of the drug. A new research project from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) has shown promise in using magnetic bacteria as a vehicle for delivering anti-cancer drugs more accurately to the birthplace of metastasis, which are characterized by anaerobic conditions due to the immense active cell division. The team took a bacteria called magnetococcus marinus (MC-1) that has the ability to sense magnetic fields besides changes in oxygen levels, allowing the bacteria to navigate along a magnetic field towards the tumor and stay in areas of low oxygen. In this in vivo mice study 55% of the bacteria successfully transported drug-loaded nanoliposomes into hypoxic regions of tumors, whereas only 2% of common nanocarriers are thought to reach the inside of a tumor. Further research is planned to determine its effects on reducing tumor size.
Tet-on inducible system comprises of an on/off switch (the antibiotic doxycycline) to remotely control CAR T cells
Genentech and BioNTech enter into worldwide strategic collaboration
Pharma giant Genentech and private biotech company BioNTech announced on 21 September their strategic collaboration to develop, manufacture and commercialized BioNTech’s Individualized Vaccines Against Cancer (IVAC®) MUTANOME clinical platform for the potential treatment of multiple cancers. Here, a patient’s cancer genome is sequenced, data is used to select a personalized set of neoantigens present in the patient’s tumor (“mutanome”) from their warehouse, and the resulting mRNA vaccine is given back to the patient with the purpose of activating the immune system to attack the cancer. Under the terms of the agreement, the subsidiary of Roche will pay the German biotech USD 310 million in upfront and near-term milestone payments. Development costs and any potential profits for certain programs under the agreement will be equally shared between the partners, with BioNTech retaining certain manufacturing and co-promotion rights.
EMA / FDA
EMA oncology drug recommendations for approval September
The Committee for Medicinal Products for Human Use (CHMP) adopted a position opinion for:
- Palbociclib (Ibrance, Pfizer) for the treatment of women with hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer. The small molecule inhibits cyclin-dependent kinases (CDK) 4 and 6 which constrains the division of cancer cells thereby halting tumor growth. In 2015, palbociclib received approval by the FDA under accelerated Priority Review and Breakthrough Therapy designation programs.
The CHMP recommended the conditional approval of:
- Olaratumab (Lartruvo, Eli Lilly Nederland) for the treatment of adults with soft tissue sarcoma, a rare type of cancer. Lartruvo is to be used in combination with doxorubicin (a chemotherapy medicine) in patients with advanced soft tissue sarcoma for whom surgery or radiotherapy is not suitable, and who have not been previously treated with doxorubicin. Lartruvo is a human IgG1 monoclonal antibody which inhibits the platelet-derived growth factor receptor alpha (PDGFRα).
- Ixazomib (Ninlaro, Takeda Pharma) for treating multiple myeloma adults who have received at least one prior treatment. Multiple myeloma is a type of blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow. The proteasome inhibitor that blocks the natural cell mechanisms forcing the cells into apoptosis, was designated Orphan Drug Designation (ODD) in September 2011 by the EMA.
FDA oncology/hematology approvals in September
The FDA modified the dosage regimen of:
- Nivolumab (Opdivo, Bristol-Myers Squibb) for the currently approved indications for renal cell carcinoma, metastatic melanoma, and non-small cell lung cancer. The former approved recommended single dose regimen (3 mg/kg IV every two weeks) of the PD1 inhibitor is now replaced by 240 mg intravenously (IV) every two weeks
EMA and FDA build a novel working group on rare diseases
The new collaboration between the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) announced was created to share best practices between the US and EU agencies and will improve the sharing of information on various aspects of the development and scientific evaluation of medicines for rare diseases. Since rare diseases affect 30 million people in the EU and a corresponding number in the US only a limited number of studies can be conducted for such small populations, both regulators are calling for more global collaboration to address a variety of issues including biosimilars, orphan drugs, and patient safety. The working group was created to focus on the design of clinical trials in small populations and the use of statistical analysis methods; the selection and validation of trial endpoints; preclinical evidence to support development programs; the design of post-marketing studies; and risk management strategies for long-term safety issues with medicines for rare diseases.