Atezolizumab better than chemotherapy in treating NSCLC in a Phase 3 clinical trial
The PD-L1 inhibitor atezolizumab (MPDL3280A, Roche) provided a survival advantage of >4 months with fewer side effects compared to the standard-of-care docetaxel in patients with advanced non-small cell lung cancer (NSCLC). According to an interim analysis of a Phase 3 clinical trial,1 subjects given atezolizumab lived an average of 13.8 months compared to 9.6 months in a control cohort.
The effect was strongest in patients with high PD-L1 levels, but clinical benefits were noted in all groups. “This is the first Phase 3 trial of a PD-L1-directed immunotherapy in lung cancer. The fact that it improves survival in patients with all categories of PD-L1 expression is highly encouraging and adds to the already known benefits of immunotherapy in lung cancer,” said senior author David Gandara of UC Davis.
Atezolizumab, together with immunotherapeutics inhibiting PD-L1's receptor PD-1, interferes with a signaling pathway that is used by NSCLC to prevent a tumor-specific immune response.
1.Rittmeyer A, Barlesi, F, Waterkamp, D, Park, K, Ciardiello, F, von Pawel, J, Gadgeel, SM, Hida, T, Kowalski, DM, Dols, MC, Cortinovis, DL, Leach, J, Polikoff, J, Barrios, C, Kabbinavar, F, Frontera, OA, De Marinis, F, Turna, H, Lee, JS, Ballinger, M, Kowanetz, M, He, P, Chen, DS, Sandler, A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2016; doi: 10.1016/S0140-6736(16)32517-X
rVSV-ZEBOV Ebola vaccine highly protective in a large-scale African trial
No Ebola cases were recorded among people vaccinated with the rVSV-ZEBOV candidate vaccine (Merck) in a Phase 3 study involving almost 12,000 people in Guinea. In contrast, there were 23 cases in the no-vaccine control cohort.
The trial took a ‘ring-vaccination’ approach, in which eligible subjects were identified as having come into contact with a person newly diagnosed with Ebola. They were tested for the disease after 10 days, and after 3 weeks the control cohort was offered a vaccine as well.
The most recent outbreak of Ebola in West Africa has accounted for >11,000 deaths, but new cases have dwindled to very few. “While these compelling results come too late for those who lost their lives during West Africa's Ebola epidemic, they show that when the next Ebola outbreak hits, we will not be defenseless,” said senior author Marie-Paule Kieny of the World Health Organization.
1.Henao-Restrepo AM, Camacho A, Longini IM, Watson CH, Edmunds WJ, Egger M, Carroll MW, Dean NE, Diatta I, Doumbia M, Draguez B, Duraffour S, Enwere G, Grais R, Gunther S, Gsell PS, Hossmann S, Watle SV, Kondé MK, Kéïta S, Kone S, Kuisma E, Levine MM, Mandal S, Mauget T, Norheim G, Riveros X, Soumah A, Trelle S, Vicari AS, Røttingen JA, Kieny MP. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). Lancet 2016; doi: 10.1016/S0140-6736(16)32621-6
Early trial shows promise for a DC vaccine against HER2-positive breast cancer
80% of breast cancer patients developed tumor-targeting immunity after they had undergone a novel dendritic cell (DC) immunotherapy as a part of a small-scale clinical trial. DCs were harvested from 54 women with HER2-expressing early-stage breast cancer, primed with HER2-derived peptides, and reinfused once a week for six weeks.1
The treatment was well tolerated and most effective in case of ductal carcinoma in situ. 13 patients showed a complete response.
HER2, which is overexpressed in about one-quarter of all breast cancers, is associated with aggressive disease and poor prognosis.
1.Lowenfeld L, Mick R, Datta J, Xu S, Fitzpatrick E, Fisher CS, Fox KR, DeMichele A, Zhang P, Weinstein S, Roses RE, Czerniecki BJ. Dendritic Cell Vaccination Enhances Immune Responses and Induces Regression of HER2pos DCIS Independent of Route: Results of Randomized Selection Design Trial. Clin Cancer Res 2016; pii: clincanres.1924.2016
Another paper linking vaccines to autism was retracted
A report that suggested a connection between vaccines and neurodevelopmental disorders, such as autism and ADHD, was withdrawn by the Open Access journal Frontiers in Public Health. The study collected data on >400 families, and based on an online questionnaire, concluded that vaccinated children are three times more likely to develop a disorders. The publisher has re-opened the review process following heavy criticism of the paper and its methodology.
Virus-based immunotherapy vocimagene amiretrorepvec enters Phase 2/3
A retroviral replicating vector vocimagene amiretrorepvec (Toca 511, Tocagen) is being tested for treatment of recurrent glioblastoma in a Phase 2/3 Toca 5 trial. This investigational immunotherapy is designed to selectively kill tumor cells and associated immunosuppressive cells, as well as to boost the immune response by releasing viral proteins and cancer neoantigens in the tumor microenvironment.
“The Phase 1 results for this treatment in patients with recurrent high grade glioma showed encouraging data including a favorable safety profile, durable tumor responses and promising survival. We now eagerly anticipate the results from the randomized Toca 5 study,” said Zvi Ram of Tel-Aviv Sourasky Medical Center.
Glioblastoma is one of the most aggressive cancers, with poor prognosis and very limited treatment options.
Nanodiscs effective in delivering cancer vaccines in mice
Synthetic high-density lipoprotein-mimicking nanodiscs coupled with cancer antigens and adjuvants effectively elicited antitumor T-cell responses in skin and colon cancer mouse models.1 When combined with checkpoint inhibitors, the therapeutic vaccine completely eliminated tumors in the majority of mice within 10 days. Moreover, cancer cells injected after 70 days were eliminated, suggesting long-term immune response.
“It's a powerful vaccine technology that efficiently delivers vaccine components to the right cells in the right tissues. Better delivery translates to better T-cell responses and better efficacy,” said co-senior author Anna Schwendeman of University of Michigan.
1.Kuai R, Ochyl LJ, Bahjat KS, Schwendeman A, Moon JJ. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat Mater 2016; doi: 10.1038/nmat4822
Nivolumab is tested with a cancer vaccine in NSCLC patients
A Phase 1 trial has started for a combination of nivolumab (Opdivo, BMS) and the experimental cancer vaccine CV301 (Bavarian Nordic) in 40 NSCLC patients who failed prior treatment. A follow-up Phase 2 study is already in the planning, which will test the combination vs. nivolumab alone in 120 subjects.
CV301 targets two antigens overexpressed in multiple solid tumors. Two doses include a vaccinia vector-based prime and fowlpox-vectored boost.
Nivolumab, a PD-1 inhibitor, has been approved in the U.S. as a second-line treatment of NSCLC, but failed a recent trial in newly diagnosed lung cancer.
Lyme disease vaccine candidate advances to clinical trials
The Lyme disease vaccine VLA15 (Valneva) has received approvals for a clinical trial from U.S. and European authorities. The vaccine, which targets the outer surface protein OspA, protected mice against the majority of Borrelia species.
Lyme disease is transmitted by tick bites. It causes skin rash, fever and headache, and can develop into persistent infection of joints, heart or the nervous tissue. It is widespread in the U.S. and Europe. VLA15 is currently the only vaccine against Lyme disease in development. A previously licensed Lyme vaccine was withdrawn from the market due to poor uptake and apparent associated adverse effects.
Cancer neoantigens identified directly by mass spectrometry
Mass spectrometry has been used successfully to identify clinically relevant neoantigens from melanoma patients.1 Compared to DNA sequencing and in silico prediction, this method seems to be faster and more accurate.
“For the first time, we have used the mass spectrometer to investigate not just expanded, cells, but rather heterogeneous tumor tissues of real patients,” says co-senior author of the study Matthias Mann of Max Planck Institute. “That gives us much more detailed information about the molecular characteristics of the tumor.”
The team sequenced almost 100,000 peptides from 25 melanoma patients. Four of the mutated peptides proved to elicit T-cell responses. This work might lead to the development of personalized vaccines or adoptive T-cell therapies.
1.Bassani-Sternberg M, Bräunlein E, Klar R, Engleitner T, Sinitcyn P, Audehm S, Straub M, Weber J, Slotta-Huspenina J, Specht K, Martignoni ME, Werner A, Hein R, H Busch D, Peschel C, Rad R, Cox J, Mann M, Krackhardt AM. Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. Nat Commun 2016; 7:13404
Peanut allergy vaccine candidate fast-tracked by FDA
The U.S. Food and Drug Administration (FDA) has granted a Fast Track Designation to the peanut allergy vaccine ASP0892 (Astellas). This DNA vaccine, which targets the lysosomal-associated membrane protein found on the surface of some immune cells, is designed to elicit a complete response including antibody and cytokine production.
Around 1.4% of U.S. children suffer from peanut allergy, for which there is no accepted way of prevention or treatment.
ASP0892 is in a Phase 1 trial assessing safety and immunogenicity. Another vaccine candidate, AR101 (Aimmune Therapeutics), is in a Phase 3 study.
Phase 1 trial tests CAR-T therapy in brain cancer patients
A clinical trial of IL13Rα2-specific CAR-T cell immunotherapy of glioblastoma has started in the U.S. It is based on a case study, in which the treatment led to regression of brain and spinal tumors and return of the patient to normal life.1
In the study, a subject with aggressive recurrent multifocal glioblastoma received CAR-T cells directly into the brain tumor. “By injecting the reengineered CAR-T cells directly into the tumor site and the ventricles, where the spinal fluid is made, the treatment could be delivered throughout the patient's brain and also to the spinal cord where this particular patient had a large metastatic tumor,” senior author Behnam Badie of City of Hope said.
In CAR-T therapy, engineered T cells with a chimeric receptor targeting a cancer-specific marker are expanded in vitro and infused back into the patient. In this case, the target protein is interleukin-13 receptor overexpressed by aggressive brain tumors.
1.Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, Kurien A, Priceman SJ, Wang X, Harshbarger TL, D'Apuzzo M, Ressler JA, Jensen MC, Barish ME, Chen M, Portnow J, Forman SJ, Badie B. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. New Engl J Med 2016; 375(26):2561-9