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Saturday, 2 June 2018

Dendritic cell vaccines: back to the future

Dendritic cell (computer generated from
EM scan)
Two news announcements in recent weeks sent me tripping down memory lane and musing on the number of once promising therapeutic concepts that have never lived up to their billing. 

At the turn of the century, dendritic cell vaccination was seen as the great leap forward for cancer immunotherapy. The concept is simple, although execution less so. The body’s recognition of infectious agents or cancer cells as being “foreign” starts with how antigens are presented to the immune system by specialised, wait for it, “antigen presenting cells”, of which dendritic cells (DCs) elicit the most potent T-cell responses. 

DCs can be readily harvested from bone marrow or peripheral blood, primed in the laboratory to recognise tumour antigens, expanded and matured in culture and then infused back into the patient, ready to kick-start a cancer-fighting cellular immune response. The challenge of commercialising DC vaccination proved to be as much logistical as immunological with only one company, Seattle-based Dendreon Corporation, successfully overcoming the hurdles of DC collection, processing and delivering adequate amounts of patient-specific vaccine, all in a manner satisfactory to regulatory agencies.  

Dendreon’s one and only product, Provenge®, received approval as a treatment for hormone-refractory (“castration resistant”) metastatic prostate cancer in 2010. While hailed as a milestone in cancer vaccine development, Provenge® was approved on the basis of a 4 month improvement in median survival over placebo, at a treatment cost of $93,000. Confusion over reimbursement, scepticism over benefit, competition from conventional chemotherapy, low margins and heavy corporate debt resulted in Dendreon filing for bankruptcy at the end of 2014, with Provenge® and the manufacturing assets being first acquired by Valeant in early 2015 and then by Sanpower Group, a Chinese conglomerate, in early 2017. 

Sanpower, while eyeing China and other new markets, is hoping that a new Provenge® study in men with early-stage prostate cancer might lead to an expanded label indication.  Prostate cancer progression is slow is most men, and “watchful waiting” is an option to surgery and/or radiotherapy. Provenge® therapy might usefully slow progression, although proof of this is at least five years away. 

A near-neighbour of Dendreon’s, Northwest Biotherapeutics is another long-standing champion of DC vaccination, its  lead product being DCVax®-L, a personalised vaccine for glioma, an aggressive form of brain cancer. DCs are primed using material from the patient’s own tumour. Northwest has a history that can reasonably be described as “colourful”, involving allegations of related party transactions, mysterious delays in the reporting data from a Phase III study first registered in 2002 (variously attributed to the Christmas holidays and a severe outbreak of flu among senior management), and a subsequent exit from NASDAQ. 

With broad, and misleadingly enthusiastic, coverage in the popular press, Northwest recently provided an update on progress in the Phase III glioma study, now in its 11th year. Well, better late than never, but as others have pointed out, it doesn’t actually say that much, being interim (and blinded) data. The data set stands at 331 subjects (DCVax®-L and placebo-treated) although interpretation is complicated by the cross-over study design, as patients with tumour recurrence (a racing certainty in glioma) were allowed to receive the vaccine. 

A breakdown of survival by factors known to influence outcome (the degree of resection, patient age and the ability to better metabolise chemotherapydrug) hints at an increase in survival , but the conclusion is no stronger than “Collectively, the blinded interim survival data suggest that the patients in this Phase 3 trial are living longer than expected”.  Proof of significant benefit awaits primary outcome data (progression-free survival). 

While a treatment that improves survival in glioma is sorely needed,  and a better-tolerated alternative to chemotherapy might be preferable for some prostate cancer patients, DCVax®-L or Provenge® successes are unlikely to lead to a renaissance in DC vaccine interest, as the spotlight has long since shifted to CAR-T and other cellular immunotherapies, small molecule and biologic immuno-oncology drugs that rekindle anti-tumour immune responses and neoantigen-based cancer vaccine strategies. 

Ironically, without the pioneering work of Dendreon, both in DC vaccine manufacturing logistics and establishing enhanced survival, the industry might never have embraced cancer immunotherapy development with anything like the current degree of enthusiasm. 

Photo credit:  Bliss, D  and Subramaniam, S. National Cancer Institute.

Updated 2nd August 2018

In what strikes me as a not easily predictable turn of events, a major Chinese retailer, Xinbai (think department store), has purchased the Sanpower biotech unit responsible for Provenge. I love the Chinese biotech industry.....

Updated 14th June 2018

Interviews conducted by Medscape Medical News suggest that GBM treatment experts remain to be convinced that DCVax®-L is likely to prove of benefit. 

Dendritic Vaccine for Glioblastoma: Hope Hyped, Say Some. Castellino, AM. Medscape Medical News. Published online 13th June 2018 (registration required to access).

An excellent commentary by Saxena et al, makes the valid point that DC vaccination  could be combined with other forms of immunotherapy and lists a number of ongoing DC vaccine/immune checkpoint inhibitor clinical studies. At the same time, given the number of variables that are likely to influence DC vaccine efficacy, optimisation will require a substantial amount of "mix and match" investigation.

Towards superior dendritic-cell vaccines for cancer therapy. Saxena, M et al. Nature Biomedical Engineering. June 2018: 2; 341–346. Published online: 11th June 2018.

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. Liau, LM et al. Transl Med (2018) 16:142. Open access. https://doi.org/10.1186/s12967-018-1507-6.

Dendreon Initiates Large-Scale Clinical Trial to Investigate PROVENGE® (sipuleucel-T) in Men with Early-Stage Prostate Cancer on Active Surveillance. Company press release online 18th May 2018. http://tinyurl.com/y98decvc.

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