Oncology Highlights - July 2018
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Enjoy reading! - The SMS-oncology team
Although epidemiological data support a link between a cancer patient’s mental state and survival, the evidence is still inconsistent as the mechanisms are unknown. A recent study in mice presents a physiological model why improvement in patient’s emotions may affect the disease progression. The reward system in the brain is composed of dopaminergic neurons in the ventral tegmental area (VTA). The VTA plays a key role in mediating positive emotions, expectations and motivation via the transmitting hormone dopamine. We know from previous pharmacological studies that there is a strong link between dopamine release and immune activity modulation. Aiming to test whether the brain’s reward system could affect tumor growth via effecting the immunity, the team studied two mouse models of cancer — one of lung cancer and the other of melanoma. The results showed that activating the VTA reduced tumor weight and volume via negatively affecting the function of myeloid derived suppressor cells (MDSCs). MDSCs act to support tumor growth by suppressing the anti-tumor immune response and by generating a favorable environment for the tumor. Their reduced functioning via reward stimuli resulted in activation of immune system to fight back. These findings shed light on the role of the mental state in the development of cancer. The study is published in Nature Communications.
BRCA1 mutations play a key role in breast, ovarian and prostate cancers and cause tumors to be hypersensitive to poly ADP-ribose polymerase inhibitors (PARPi) through to loss of homologous recombination. However, some patients develop resistance against PARPi or do not even respond to them from the start. Aiming to identify the genes driving this, Professor Steve Jackson and colleagues - the same scientists who developed the PARPi - used CRISPR-Cas 9 gene editing to screen breast cancer cells with BRCA1 mutation. They found the protein complex referred to as Shieldin was depleted in PARPi resistant tumors. Shieldin is involved in non-homologous end-joining (NHEJ) and the tug-of-a war between the NHEJ and Homologous Recombination (HR) mechanism in patients with BRCA1 mutation renders cancer cells susceptible to PARPi. In a subset of patients, Shieldin levels are low or mutated which results in tumor cells to regain performing HR and hence develop the resistance to PARPi drugs. To confirm this, the team used xenograft models with low levels of Shieldin. Indeed, mice transplanted with these biopsies evolved to be non-responding to PARPi. Furthermore, researchers also explored the vulnerabilities of PARPi resistant cells to alternative cancer treatments, such as radiotherapy or platinum-based chemotherapy. These findings will improve personalizing therapies for a patient its specific tumor genotype. The study is published in Nature Cell Biology.
Genetically reprogramming T cells for therapeutic purposes is difficult. Unspecific methods such as recombinant viral vectors slowed down research and clinical use as their manufacturing and testing has been proven lengthy and expensive. For the first time, scientists developed a swift CRISPR–Cas9 system that efficiently and precisely removes genes from white blood cells and enables to insert beneficial replacements in a very short time period. Instead of viral vectors, both the both gene-editing tools and new genetic material are delivered via electrical field speeding up the process and preserving cell viability. In their paper, they apply this technique to engineer T-cells to recognize human melanoma cells and further proof in mice model that the modified T-cells were able to attack xenograph melanoma. If the technique is proven easy to apply in other labs, it may open up new therapeutic possibilities for treating cancer, as well as for infections like HIV and autoimmune conditions. The study is published in Nature.
The link between nutrition and cancer is nothing new, however, most studies so far focused on types of foods (eg, fruits and vegetables) and the role of quantity of food intake in cancer incidence. In a recent population-based case control study conducted in the Barcelona Institute for Global Health (ISGlobal), disturbances in circadian rhythm and the timing of the food intake before sleep were examined. A group of 621 cases of prostate and 1205 cases of breast cancer patients were interviewed on their lifestyle. Results indicated that cancer risk is decreased with increasing time between supper (main evening meal) and sleeping. Specifically eating dinner before 9 pm and going to bed at least 2 hours after the meal significantly lower the risk for both breast and prostate cancer for 20% combined. The findings suggest that changes in circadian controlled activities have profound effects on homeostasis including transcriptome content and the metabolome. A similar association is shown between the night shift work and sleep deprivation and cancer occurrence. The strength of the study is the large sample size and detailed questionnaire on circadian rhythm and diet. Findings are specifically important for southern European cultures where people have supper late. The study is published in International Journal of Cancer.
Forbion, a European life science venture capital firm with offices in The Netherlands and Germany, raised €270M in the latest round named Forbion IV. Although the fund is explicitly Eurocentric, 20% of Forbion IV will be allocated to North American businesses. Forbion plans to feature a portfolio of 15 companies of which 10 can help transform into high-return businesses (“growth” opportunities), and 5 companies built from scratch (“build” opportunities). Previous fund bet on I/O biotech Rigontec (acquired by Merck for €463M); and another I/O startup Replimune (raised in US IPO $100M) points out the success of Forbion in biotech investments. Forbion becomes the third European biotech venture fund to land more than $900M in total. Experts see European Biotech space to be healthy however lagging behind the US in terms of public markets. To compete with this, Forbion and others aim to accelerate the ecosystem in Europe. In July, UK its Wellcome Trust, a charitable foundation secured $330M Leap Fund to invest in high-risk healthcare and life science research. Previously in May 2017, Vesalius Biocapital, a life sciences venture capital investor based in Luxembourg, announced Vesalius Biocapital III closing in €65M with plans to invest in late-stage life sciences companies. These examples indicate that the venture capital community in Europe is growing. Although Europe possesses world-class scientists, lack of European capital results in premature acquisitions of small biotech by big players not allowing to build up the value of their experimental medicines. Forbion and other local funds aim to support firms to stay independent.
Strategic collaborations and acquisitions in CAR-T space: Kite Pharma and Gadeta; Sangamo and TxCell
Kite Pharma and Gadeta announced a strategic collaboration to develop immunotherapies with T cells to target solid tumors. Kite, a Gilead company and CAR-T cell front runner, has developed Yescarta which now also available in European market for the treatment of non-Hodgkin lymphoma. Gadeta is a privately-held biotech focusing on engineering alpha beta (αβ) T cells with gamma delta (δγ) T cell receptors called TEGs for the development of cancer immunotherapies. Gadeta’s platform combines best of two worlds: advantages of conventional T cells that recognize novel targets in cancer cells - without the need of a surface epitope recognition. Kite will support Gadeta with research and development funding and future payments will be eligible upon achievement of milestones. As CAR-T therapy space gaining acceleration, Sangamo Therapeutics is set to take over the French biotech company TxCell for its CAR-Treg platform and pipeline in €72M deal. Although currently CAR-Treg platform is being developed for autoimmune and Graft versus Host diseases, it has the potential to be applied in 100+ diseases. The platform is unique with inserting CAR receptors in to Tregs, the cells control the immune system responding to foreign particles. Sangamo plans to apply its zinc finger gene editing technology to TxCell’s cells. Although TxCell is not yet in the clinic, Sangamo is convinced with its preclinical evidence and expects to close the deal in the Q4 2018.
The Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorizations for:
- Encorafenib and binimetinib (Braftovi and Mektovi, Pierre Fabre) to be used in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Combining BRAF inhibitor and MEK1/2 kinase inhibitor was shown to prolong progression-free survival and overall survival.
- Durvalumab (Imfinzi, AstraZeneca) for the treatment of non-small cell lung cancer (NSCLC). Approval comes after the positive results of PACIFIC phase III trial with PDL1 inhibitor showing significant increase overall survival for these patients.
- Abemaciclib (Verzenios, Eli Lilly) for the treatment of locally advanced or metastatic breast cancer. The CDK4/6 inhibitor is specifically beneficial in combination with an aromatase inhibitor or fulvestrant.
The CHMP recommended granting a marketing authorisation for the generic medicines:
- Gefitinib (Gefitinib Mylan, Mylan) for the treatment of NSCLC. The EGFR inhibitor demonstrated satisfactory bioequivalence to its reference Iressa, a small molecule also targeting EGFR.
- Lenalidomide (Lenalidomide Accord, Accord Healthcare) for the treatment of multiple myeloma. The generic of Revlimid is an immunomodulation agent affecting cytokine modulation, induction of T-cell proliferation, anti‑proliferation of multiple myeloma cells and inhibition of angiogenesis. The authorization was accompanied with the recently resolved patent agreement between Celgene and Accord Healthcare. The deal between the drug makers protects Celgene's Revlimid sales through early 2022.
The CHMP recommended extensions of indications for:
- Blinatumomab (Blincyto, Amgen) as mono therapy for the treatment of paediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-cell precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.
- Dabrafenib (Tafinlar, Novartis) as an adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
- Pembrolizumab (Keytruda, Merck) in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations.
The FDA granted regular approval for:
- Ivosidenib (Tibsovo, Agios) for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test therapy. The inhibitor of the IDH1 enzyme is the first and only FDA approved therapy for patients with R/R AML and an IDH1 mutation.
- Ribociclib (Kisqali, Novartis) in combination with an aromatase inhibitor for pre/perimenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy. Selective CDK4/6 has been shown to overcome or delay resistance to endocrine therapy and previously was approved in postmenopausal women.
- Enzalutamide (Xtandi, Astellas) for patients with castration-resistant prostate cancer (CRPC). The approval is based on the PROSPER phase III trial, in which the combination of this androgen receptor antagonist and androgen deprivation therapy (ADT) reduced the risk of metastases or death.
- Ipilimumab and Nivolumab (Yervoy and Opdivo, Bristol-Myers Squibb) to use in combination with nivolumab for the treatment of patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The IO/IO combination was approved based on overall response rate and duration of response (DOR) and is also approved for patients with intermediate or poor risk renal cell carcinoma and patients with unresectable or metastatic melanoma.