Melanoma immunotherapy: Can vaccines and cell therapies expand on immune checkpoint inhibitor successes?

Mestastatic melanoma cells

Tracking the major cancer meetings has kept me occupied throughout October and into November but left me with plenty of material for this, and future, blog articles. A presentation at the UK’s NCRI conference on the increasing mortality rate from melanoma in men (but not women, where mortality rates are generally declining or stabilising), while alarming, did remind me of just how far melanoma treatment has advanced in a few short years.  

Prior to the availability of anti-CLTA-4 and anti-PD-1 immune checkpoint inhibitors, overall survival from metastatic melanoma in developed countries was around 25% after three years: combination immune checkpoint inhibitor treatment has stretched this to over 60%, and use following surgery (“adjuvant” use) significantly improves recurrence free survival.

Despite these successes, a significant need remains for alternative treatments for those who fail, or are intolerant of, current immune inhibitor checkpoint regimens and a gamut of investigational immunotherapies including “personalized” or “individualised” peptide and mRNA therapeutic vaccines, cell therapies and oncolytic virus therapies are in active clinical development.

That the immune system recognises melanoma as being “not self” has been known for decades and means of usefully exploiting this distinction long precede the discovery of immune checkpoints. Attempts to effectively boost the anti-melanoma immune response through injection of the Bacille Calmette–Guérin (BCG) tuberculosis vaccine were made in the 1970s, with mixed success. The potent immunomodulators, interferon alpha (IFNα) and interleukin 2 (IL-2), were approved for use in melanoma in the 1990s and still have a role in the treatment of metastatic disease and adjuvant therapy.

Melanoma has long been an attractive target for cancer vaccine development. A variety of melanoma antigens common to a majority of tumours - “tumour-associated antigens” (TAAs), including gp100, GM2; tryosinase, MART-1 and MAGE-A3, have been exploited, either alone or in combination, in cell-based and peptide therapeutic vaccines.

Cell-based vaccines (as either intact or processed tumour cells or as cell-free lysates) offer the advantage of presenting a spectrum of TAAs, although neither patient-derived (autologous) nor cultured tumour cell-derived (allogeneic) cell-based melanoma vaccines, such as Melacine® (GSK/Schering) and Canvaxin® (CancerVax/Serono), have made it through pivotal studies. M-VAX (AVAX), a chemically-modified autologous cell vaccine, has been in late-stage development limbo for over a decade.

Historically, peptide vaccines have fared no better, with a pivotal study of Oncophage® (Antigenics), the manufacture of which involved isolation of heat shock protein-peptide complexes from autologous tumour cells, being abandoned, and a Phase III study of a MAGE-A3 peptide vaccine (GSK) being terminated due to lack of obvious efficacy over placebo.

Adoptive cell transfer (ACT) involves the collection, isolation, ex vivo expansion and (re)-infusion of autologous tumour-associated cytotoxic T-cells. ACT using tumour-infiltrating lymphocytes (TIL) has occasionally attained response rates of 40%-50% and complete remission in 10% to 25% of patients with extensive metastatic disease: however, the complexity of ACT has essentially confined it to clinical studies and compassionate use.

As is the case with other cancer indications, decades of disappointment and inconsistency have not curbed the academic and commercial pursuit of effective melanoma immunotherapies. Applying recent advances in technology- next generation sequencing; gene transfer and editing; nucleic acid delivery- to melanoma vaccine and cell therapy development might just make these old dogs capable of new tricks.

Cancer vaccine efficacy is blunted by the immunosuppressive tumour microenvironment: combination with immune checkpoint inhibitors is an obvious means of increasing the odds of success and a number of studies combining therapeutic vaccines with anti-PD-1 or anti-CTLA-4 immune checkpoint inhibitors are underway. These agents may eventually be joined or replaced, by one or more of the “next wave” of immune-oncology drugs directed at LAG3, CSF1-R, GITR or at targets in the innate immune systems which can fire up the immune response.

Imlygic® (T-VEC: Amgen), an oncolytic virus therapy is“vaccine-like” in effect, activating both the innate immune system and revealing hidden tumour antigens (“neoantigens”) to the adaptive immune system through tumour lysis. Combination with ipilimumab has shown improvement in response rates over Imlygic® alone, and a Phase III combination study with pembrolizumab (KEYNOTE-034) is ongoing. Early-stage studies of CAVATAK®, an investigational virotherapy acquired by Merck & Co from Viralytics earlier this year, has shown promise when combined with either pembrolizumab or ipilimumab.

The application of next generation sequencing technology and bioinformatics could offer a practical route to bespoke melanoma vaccines, with antigen selection and vaccine composition being determined by tumour and patient genetic makeup. Neon Therapeutics is currently trialling a synthetic peptide vaccine (NEO-PV-01) using sequencing of tumour biopsy material to formulate a selection of up to 20 peptide-mimicking patient-specific neoantigens. NantBioScience is pursuing a similar personalization strategy, with expression of patient-specific neoantigens in yeast cells (YE-NEO-001).

The in vivo expression of melanoma (and other cancer antigens) through the introduction of the corresponding mRNA sequence is receiving increasing attention. Lipid complex mRNA vaccines, encoding multiple melanoma TAAs or a personalised selection of antigens, are now in early clinical studies (Lipo-MERIT and RO7198457: BioNTech).

mRNA has brought a new twist to dendritic cell (DC) vaccination, where DCs isolated from the patient are loaded with melanoma antigens to optimise their processing and efficiency of presentation to the immune system. eTheRNA’s TriMix technology combines mRNA encoding melanoma antigens with mRNA encoding proteins known to enhance DC activation and maturation and to promote both helper and cytotoxic T cell production. Durable clinical responses have been achieved in melanoma patients who had failed previous treatments when the TriMix-DC-MEL vaccine was administered in combination with ipilimumab.

Gene transfer may open up additional ACT strategies for melanoma. T-cell receptor (TCR) gene transfer allows the generation of antigen-specific lymphocytes from patient T-cells Early studies with melanoma antigen-specific TCRs have shown modest response rates, although several have been marred by severe adverse events due to the “off-target” destruction of normal melanocytes.

The utility of ACT may be significantly improved through chimeric antigen receptor (CAR-T) technology, where T-cell antigen receptors are engineered to combine binding, signalling and co-stimulatory domains. Pilot CAR-T studies are underway. Improvements in TIL ACT may be possible by using CRISPR-CAS9 gene editing to increase the ability of T-cells to home in on tumours.

Next generation cell therapies, including DC vaccination, are likely to benefit from the broader expanding commercial interest in CAR-T and TCR therapies which will likely lead to further improvements in manufacture and assist in establishing the logistics necessary to delivery patient-specific treatments. Growing use of semi- or wholly-automated cell product processing will ultimately reduce costs and make the treatment of larger number of patients viable.

Effective melanoma immunotherapy had been a long time in coming, but as immune checkpoint inhibitor therapy has shown, revolution is possible. Experimental melanoma immunotherapies still have a lot to prove, but with the aid of across the board advances in immuno-oncology and other disciplines, we may finally see vaccine and cell-based approaches becoming practical and valuable treatment options.

Photo credit: Valencia, JC. NCI Center for Cancer Research

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.