Oncology Highlights - November 2017
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!
The SMS-oncology team
Tethering and injecting immunotherapy: A novel approach that limits the complications
In the past five years, checkpoint inhibitors revolutionized the treatment for wide range of cancers. However, these drugs often trigger troubling autoimmune responses as they are administered intravenously. Jeffrey Hubbell and colleagues developed a novel approach to improve the specificity of the immunotherapeutic agents. Conjugating the binding domain of “super affinity peptide” - placenta growth factor-2 (PlGF-2) to anti-CTLA4 and anti-PD-L1 -, they succeeded on increasing the penetration of modified drugs in the tumor matrix. In order to avoid the systemic auto-immune effect, drugs were injected directly into the tumor tissue. Preclinical results in mice showed that the modified drug-antibody model slowed growth of implanted tumors and extended survival with reduced adverse events. This simple and translatable approach of engineered Extra Cellular Matrix (ECM)-binding Abs may present a viable and safer approach in checkpoint blockade. The study was published in Science Translational Medicine.
Fat cell maybe hampering chemotherapy
The link between diet and the chemotherapy efficieny has become a research interest not so long ago. Obesity is also shown to be associated with poorer prognosis. In a recent study, scientists show that a very common chemotherapeutic agent, daunorubicin was absorbed and metabolized by adipocytes from the tumor microenvironment (TME). Daunorubicin is an anthracycline that is used for treatment of a variety of cancers including leukemia. Analysis of the daunorubicin pharmacokinetics in cultured adipocyte cells and tissue indicated the conversion of daunorubicin to its inactive metabolite, daunorubicinol. Fat cells express high levels of AKR and CBR isoenzymes that deactivate anthracyclines. These results could be clinically important for adipocyte-rich cancer microenvironments such as omentum, breast, and marrow. The study was published in Molecular Cancer Research.
The dark side of PD-1 inhibition
A new study published in Nature reports the complications of the immunotherapy game in cancer. Using a mouse model for T cell Non-Hodgkin Lymphoma (T-NHL), scientists uncovered a previously unknown role of PD-1 in T-cell cancers. Researchers introduced random mutations to the whole T cell genome to mimic the mutational burden of cancer. Results showed that interfering PD-1 signaling induced the proliferation of cancerous T cells. Mechanistically, inactivation through regular PD-1 pathway in T-NHL model does not protect the tumor but rather stops the proliferation. Anti-PD-1 treatment and/or loss of PD-1 signal benefits the cancerous T cells. This observation explains the correlation between the aggressiveness of the tumors with PD-1 mutations. In the era of immune-based cancer therapies, Wartewig and colleagues’ study raises an important point: improving our understanding of immunotherapy will reduce the possible harmful side effects.
EMA is moving to Amsterdam. What does this entail for the Netherlands?
Amsterdam will be the new home of the European Medicines Agency after a down-to-the-wire vote that was settled by drawing names from a bowl. EMA is one of the most coveted organizations in Europe, thanks to its role at the heart of the EU drug approval system and the massive research and development industry it feeds. The agency also drives business tourism, with more than 30,000 experts flying in for EMA meetings every year. Now all eyes will be on Amsterdam, as the move itself is also a challenge due to tight time frame: Operations in Amsterdam are scheduled to start by 30 March 2019. But what’s the real impact of EMA’s relocation to the city of canals? It is likely that Amsterdam will see an increase in pharmaceutical industry jobs. A greater impact might be on the pharmaceutical / medtech companies weighing up their clinical research investments. In a positive scenario, this strategical move might be a major source of revenue and employment for the Netherlands.
The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for:
- Fulvestrant (Fulvestrant Mylan, Mylan) is a generic for the treatment of estrogen receptor positive, locally advanced or metastatic breast cancer in postmenopausal women that is not previously treated with endocrine therapy, orwith disease relapse on or after adjuvant antiestrogentherapy, or disease progression on antiestrogen therapy.
- Bevacizumab (Mvasi, Amgen) the first biosimilar, for the treatment of adult patients with metastatic carcinoma of the colon or rectumin combination with fluoropyrimidine-based chemotherapy, or in combination with paclitaxel for first-line treatment of adult patients with metastatic breast cancer, or in addition to platinum-based chemotherapy, for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology.
The Food and Drug Administration adopted a positive opinion for:
- Alectinib (Alecensa, Hoffmann-La Roche, Inc./Genentech), for treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In December 2015, alectinib received accelerated approval for treatment of patients with ALK-positive metastatic NSCLC whose disease progressed on or who were intolerant of crizotinib based on an independent review committee (IRC)-assessed overall response rate (ORR) of 38% and 44% among 87 and 138 patients, respectively, in two single arm trials.
- Brentuximab vedotin (Adcetris, Seattle Genetics) for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy. In August 2011, this ADC received an accelerated approval in the treatment of relapsed HL and ALCL.
- Dasatinib (Sprycel, Bristol-Myers Squibb) for the treatment of pediatric patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase. Dasatinib is a Bcr-Abl (the "Philadelphia chromosome") and Src family tyrosine kinase inhibitor approved for first line use in adult patients with same phenotype.
- Obinutuzumab (Gazyva, Genentech) in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma (FL). Obinutuzumab (called afutuzumab until 2009) is a humanized anti-CD20 monoclonal antibody.
Sunitinib malate (Sutent, Pfizer Inc) for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma following nephrectomy. Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor.