Background Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer. Methods In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. Results In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P = 0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P = 0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P = 0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache. Conclusions The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)

/pdf/sipuleucel-t-immunotherapy-for-castration-resistant-prostate-31dll2jbjc.pdf

Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, noncavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin's barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase its impact on medicine.

/pdf/transdermal-drug-delivery-3e333n59sf.pdf

Transdermal drug delivery

mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use.

/pdf/mrna-vaccines-a-new-era-in-vaccinology-7vmxaaclmy.pdf

mRNA vaccines — a new era in vaccinology

A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.

Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy

The cancer vaccine field is littered with promising products that failed to show clinical efficacy. Could it finally be on the verge of a first US approval?

The cancer vaccine roller coaster

With the first readouts of trials of antibodies against COVID-19 appearing and others coming thick and fast, Nature Biotechnology asked a group of experts to comment on the challenges and timelines for these products.

/pdf/covid-19-antibodies-on-trial-13cl3rn0r3.pdf

COVID-19 antibodies on trial.

Disputes over how to assess a foodstuff's safety continue to play into public fears about transgenic crops.

http://www.miscugli.it/public/componenti/947/files/How%20safe%20does%20transgenic%20food%20need%20to%20be%20(SC%202808)%20.pdf

How safe does transgenic food need to be

can be done with nonspecific corticosteroids with or without Actemra (tocilizumab), an anti-IL-6R antibody, approved in several autoimmune indications. But the emphasis at the moment is on patient parameters rather than the therapy itself. Mackall and colleagues recently published system factors in patient characteristics—tumor burden, age, co-morbidities—and prescribes when to give supportive care and when to treat aggressively. What no one knows is whether CRS is essential for maximal effect. Mackall believes some CRS toxicity is needed. “I’m used to being an oncologist, you don’t have any pain, you don’t have any gain,” she says. This notion has kept physicians from using immunosuppression prophylactically, for fear of subverting the therapy. Clearly, much more needs to be learned about the biology. “What will be critical about the more therapy-specific issues are variables like the degree of T-cell expansion in vivo,” says Mark A grading scheme to predict toxicity to chimeric antigen receptor T (CAR-T) cell therapies published on May 29 is a bold attempt to manage one of the most promising immunotherapy approaches to fight cancer. Crystal Mackall, chief of pediatric oncology at the National Cancer Institute, and colleagues from multiple institutions came up with the scheme (Blood doi:10.1182/blood-2014-055527292014, 2014) after clinical trials by investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York were put on temporary hold in March due to several infusion-related patient deaths. “[The clinical hold] made it clear that if we don’t get a handle on this toxicity, even this very potent therapy could self-destruct,” Mackall says. Earlier this year, the MSKCC group and other New York–based cancer centers also defined a staging system designed to prevent or limit the toxicities that may develop with these therapies (Sci. Transl. Med. 6, 224ra25, 2014). The deaths should have come as no surprise to anyone following the field of immunotherapy, since in 2006, the (now defunct) British company TeGenero, nearly killed six healthy volunteers in a phase 1 study of an anti-CD28 monoclonal antibody, TGN1412, being tested for use in B-cell tumors and autoimmune disorders. What CAR-T cells and TGN1412 have in common is that they both lead to T-cell expansion in vivo, which can in turn lead to the release of toxic levels of cytokines, referred to variously as cytokine storms or cytokine release syndrome (CRS). Infusion reactions are common with antibody therapeutics, with symptoms ranging from mild nausea and fever, to lifethreatening multiple organ failure, as seen with TGN1412 and more recently with some CAR-T cell therapies. After agreeing with the US Food and Drug Administration to tweak the protocol, the MSKCC trials resumed in April. The dose of the therapy is being reduced in patients with large tumor burdens, as tumor burden seems to correlate with the severity of CRS. Patients with pre-existing conditions, such as cardiac problems, would not be eligible for the trial, and the length of time between induction chemotherapy and the application of CAR-T cells will be cut in half. Treatment CAR-T cell therapy seeks strategies to harness cytokine storm

Laura DeFrancesco

Papers

The cancer vaccine roller coaster

COVID-19 antibodies on trial.

How safe does transgenic food need to be

CAR-T cell therapy seeks strategies to harness cytokine storm.

Landmark approval for Dendreon's cancer vaccine.