Monoclonal antibodies and cytokines are the main weapons so far in arming the immune system to fight cancer cells. Dr Sarah Houlton considers a third option: dendritic cells
Lymphocytes can be activated to recognise antigens present on the surface of the cancer cells and attack them
Immunotherapy is an increasingly important strategy for fighting cancer. The body’s own immune system is encouraged to attack tumours, via cancer antigens on the surface of the cancer cells that distinguish them from healthy cells. There are several ways in which this can be done. The most widespread in clinical practice is the use of monoclonal antibodies that bind to the cancer antibodies; many familiar products fall into this category, such as trastuzumab (Herceptin), alemtuzumab (Campath), rituximab (Rituxan/MabThera) and bevacizumab (Avastin). Cytokines, notably the interferons and the interleukins, can also be used to alter a tumour’s immune response.
There is a third alternative – cell-based therapies. Dendritic cells were discovered in the early 1970s by Canadian scientist Ralph Steinman at Rockefeller University in New York, a discovery that won him a share in the 2011 Nobel prize in physiology or medicine.1 They essentially act as a switch that turns the immune system on and off. They pick up foreign antigens from invading cells, and then activate the T-cell lymphocytes with these antigens so they are primed to destroy the alien cancer cells bearing these antigens.
The first Phase III trials on a dendritic cell therapeutic were not promising
Early attempts to use dendritic cells as cancer vaccines were carried out in the 1990s by Edgar Engleman and Ronald Levy at Stanford University. They isolated dendritic cells from patients suffering from non-Hodgkin lymphoma for whom chemotherapy had not worked. The cells were loaded with antigen via immunoglobulin idiotype from their tumour, before being injected back into the patient. Two of the first six patients achieved a complete remission, and most experienced at least some form of T-cell mediated immune response to the tumour-specific antigen with which the dendritic cells had been loaded.
The first Phase III trials on a dendritic cell therapeutic were not promising, however. Two late-stage studies on Cell Genesys’ GVAX product in prostate cancer were stopped early in 2008 as mortality rates were higher in the treatment group who were being given GVAX plus chemotherapy, than the control group who were administered chemotherapy alone.
GVAX comprises granulocyte-macrophage colony stimulating factor (GM-CSF, an immune signalling factor that helps the cells mature) gene transduced allogeneic irradiated cancer cells and RNA/peptide loaded cells. The product had also been evaluated in a range of other cancers, including pancreatic, lung and renal tumours, melanoma and multiple myeloma. Indeed, dendritic cell discoverer Steinman was being treated with GVAX plus ipilimumab (Bristol-Myers Squibb’s immunostimulant monoclonal antibody ipilimumab, which is now marketed as Yervoy for the treatment of metastatic melanoma) for his pancreatic cancer, surviving for more than four years, before sadly dying just three days before the Nobel announcement in Stockholm – as the committee was unaware of his death, the award stood, even though Nobel prizes are not normally awarded posthumously.
The product is still being investigated, now by Aduro Biotech, in metastatic pancreatic cancer. They are administering the cell therapy in combination with the immunotherapy product CRS-207, a live, attenuated strain of listeria engineered to express the tumour-associated antigen mesothelin. Results of a Phase II trial were announced at the ASCO gastrointestinal cancers symposium in San Francisco earlier this year.2 A total of 90 patients with metastatic pancreatic ductal adenocarcinoma were treated, either being given two doses of GVAX followed by four of CRS-207 every three weeks, or six doses of GVAX. The median overall survival was six months for the combination, and four for GVAX alone, and the effect was particularly noticeable in heavily pretreated patients. Phase IIb trials are now underway.
It is also being investigated in combination with cyclic dinucleotides (CDNs). These are based on molecules made by human cells in response to DNA binding in the cytosol, activating innate immunity by inducing the expression of cytokines including Type I interferon. GVAX provides the tumour antigens while the GM-CSF attracts dendritic cells, which are activated by the CDN, resulting in antigen loaded activated dendritic cells. This combination is still in the preclinical stages of development.
The immune system is being used increasingly to develop effective methods of destroying cancer cells
Where GVAX works by activating dendritic cells in the body, other technologies involve the creation of activated autologous dendritic cells ex vivo before returning them to the patient. The idea is to take immune cells from the cancer patient, either from the tumour itself or from their blood, and then grow tumour-specific immune cells in vitro before returning them to the patient, ready to fight the cancer by generating an immune response.
Although various products and ideas are in development, thus far only one has gained regulatory approval. Sipuleucel-T (Provenge), created by Seattle-based Dendreon, is an autologous cellular immunotherapy based on dendritic cells taken from the patient. It is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer.
To create the treatment, first of all white blood cells are harvested from the patient via leukapharesis, with the cells removed from the blood and the remainder returned to the circulation. These dendritic cells, a form of antigen-presenting cell, are then incubated with the fusion protein PA2024, which combines an antigen present in almost all prostate cancer cells, prostatic acid phosphatase, or PAP, with GM-CSF. This activates the cells, and they are then returned to the patient via infusion, ready to trigger that immune response against any cancer cells that bear the PAP antigen. The patient will be given three cycles of treatment, at two-weekly intervals.
Several biotech companies are also working on potential cancer therapies based on dendritic cells
Its potential impact on these late-stage prostate cancer patients was proved in clinical trials, including a Phase III study in 512 patients with the appropriate form of the cancer.3 Those treated with the cell-based product had a median survival of 26 months, while those given placebo survived a median of 22 months, a statistically significant improvement in survival. Its potential is also now being investigated in combination with ipilimumab, and undergoing trials in a variety of other cancer indications.
Several other biotech companies are also working on potential cancer therapies based on dendritic cells. Like Dendreon’s strategy, all rely on modifying the patient’s own harvested dendritic cells in some way so that they present tumour-specific antigens to T-cell lymphocytes, which in turn are activated to recognise these antigens present on the surface of the cancer cells and attack them.
Neostem is developing its lead candidate, melapuldencel-T, for malignant melanoma. The aim is to present the patient’s immune system with the whole spectrum of antigens from their tumour. The cell collection process involves the separation of those cells that are self-renewing – in other words, those cancer stem cells that cause metastasis – and the immune response is generated against these. The cells are irradiated, and then connected to dendritic cells to activate the T-cell lymphocytes. In contrast to those immunotherapy antibodies like ipilimumab used in melanoma patients, which stimulate or reactivate the immune response to tumour antigens, it induces and enhances recognition of the whole spectrum of tumour antigens expressed on the cancer stem cells.
In a Phase II trial, patients with metastatic melanoma and for whom an autologous melanoma cell line was available were randomised to receive irradiated autologous proliferating tumour cells, or autologous dendritic cells loaded with the antigens from the tumour cells.4 In each case, the cells were administered in conjunction with 500µg of GM-CSF via subcutaneous injection every week for three weeks, and then every month for a further five months. At initial analysis, with patients followed for at least six months after randomisation, half had died, but survival was better in the dendritic cell arm – the two-year survival rate was 72%, compared with 31% of those given the irradiated proliferating tumour cells as a cancer vaccine.
The treatment was well tolerated, and the company is now planning Phase III trials. It also believes the strategy could have potential in other forms of cancer; a Phase II trial in ovarian cancer is planned, and another in non-small cell lung cancer being contemplated. Liver cancer is another possibility.
Argos Therapeutics is also developing cancer therapies based on dendritic cells. Autologous dendritic cells are harvested from the patient via leukapheresis, and antigens for the cancer isolated from a small sample of tumour or blood. Its proprietary technology, termed Arcelis, is used to isolate RNA from the tumour or blood sample for use as the antigen payload in the dendritic cells, and then the cells electroporated with the amplified tumour mRNA plus synthetic CD40L RNA. Once activated with the antigens, the dendritic cells are suspended in the patient’s own plasma ready for intradermal injection.
Its furthest advanced product candidate, AGS-003, is now in Phase III trials for kidney cancer, following positive results in Phase II. In the open label study in 21 patients with newly diagnosed and metastatic clear cell renal cell carcinoma, the autologous cell product was given every three weeks for five doses, and then every 12 weeks until progression, in conjunction with sunitinib treatment in a four weeks on, two weeks off schedule.5 The median progression free survival was 11 months, and the median overall survival 30 months. A third of the subjects were still alive four years after they started the trial, and at the time of analysis, five had reached or were nearing the five-year-plus survival point.6
Compared with historical controls, adding AGS-003 to sunitinib increased progression-free survival by a half, and doubled the expected median overall survival. The company now plans a Phase II trial in non-clear cell renal cell carcinoma, early stage renal cell carcinoma, and other solid tumours, and in October it broke ground on a manufacturing facility in North Carolina’s Research Triangle Park to support its development and commercialisation.
Malignant melanoma is the target for Neostem’s lead candidate, melapuldencel-T
Northwest Biotherapeutics is another company focusing on harnessing dendritic cells in cancer treatment. The Bethesda, Maryland-based biotech company’s platform technology, DCVax, again uses leukapheresis to harvest cells from the patient, before loading with antigen derived from the patient’s own tumour before administration via intradermal injection to activate the immune system to fight the cancer cells.
Its lead product, DCVax-L, a lysate protein extract from the tumour is used to provide the cancer antigens, providing a full range of tumour antigens and thus minimising the potential for cancer cells to evade detection as their antigens are not presented. Two Phase I/II clinical trials have been carried out in glioblastoma multiforme, including 20 patients with newly diagnosed tumours, and a further 19 with recurrent glioblastoma multiforme and other gliomas. DCVax was administered in conjunction with standard of care, and the median time to tumour recurrence was in the time-frame of two years, about three times as long as is typical for standard of care alone.7 Median survival was about three years, more than twice the normal survival with standard of care treatment. At the last long-term data analysis in 2011, one-third had reached or exceeded four years’ survival, and just over a quarter reached or exceeded six years. By 2014, two had exceeded a decade of survival, in comparison with the median survival of 15 months with full standard of care treatment.
A double blind, randomised, placebo-controlled Phase III trial is now underway in 348 patients with newly diagnosed glioblastoma multiforme, with a primary endpoint of progression free survival. Phase I trials have also been completed in metastatic ovarian cancer. The expectation is that it will be appropriate for use in patients whose tumours have been surgically excised to ‘mop up’ any residual or circulating cancer cells that could cause the tumour to return or metastasise.
An alternative product, DCVax-Direct is also being developed for direct injection into tumours that are deemed inoperable, either because removal is too difficult or risky, or because there are so many tumours it is impractical. This is all too common in those forms of cancer that are either locally advanced or metastatic by the time they are discovered, as is all too often the case with lung, pancreatic, colon, liver and ovarian cancers. Rather than pre-exposing the harvested cells to cancer antigens outside the body, the cells are partially matured after harvesting and then injected directly into the tumour, ready to collect the antigens directly from the tumour. They are then ready to activate the T-cell lymphocytes in the same way as DCVax-L.
A Phase I/II trial is currently underway in 60 patients with a variety of inoperable solid tumours. The primary goal is to achieve efficacy in terms of tumour shrinkage or elimination, and the expectation is that if regression is going to happen it will do so quickly – within the first two months of treatment.
A third product, DCVax-Prostate, is designed, as the name suggests, to treat prostate cancer – specifically late-stage non-hormone-dependent prostate cancer, in which micro-metastases have spread outside the prostate. There is a problem here with the collection of tumour tissue to create a tumour lysate as there is rarely a tumour that can be surgically removed, and there is rarely a tumour suitable for direct injection, either. To overcome this, a DCVax version has been created using prostate specific membrane antigen, found in most cancers of this type. The antigen is made via recombinant technology, and then used to arm autologous dendritic cells. The product has completed Phase II trials, and is awaiting partnering for Phase III evaluation.
1. R.M. Steinman and Z.A. Cohn J. Exp. Med. 1973, 478, 460
2. D.T. Le et al. J Clin Oncol 2014, 32 (suppl. 3), Abst 177
3. P.W. Kantoff et al. New Engl. J. Med. 2010, 363, 411
4. R.O. Dillman et al. J. Immunother. 2012, 35, 641
5. R.A. Figlin et al. J Clin Oncol 2012, 30 (suppl. 5), Abst. 348
6. A. Amin et al. J Clin Oncol 2014, 32 (suppl.), Abst. 4524
7. S. Polyzoidis and A. Keyoumars Hum. Vaccin. Immunother. 2014, 10, epub ahead of print