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Developing therapeutic cancer vaccines

Dendreon’s success has paved the way for new candidates
Pipeline

Therapeutic cancer vaccines represent a new era in cancer immunotherapy, and are designed to equip a patient's immune system to treat an existing cancer.

Sipuleucel-T (Provenge; Dendreon) is the only therapeutic vaccine commercially available in the US. It was approved by the US Food and Drug Administration (FDA) in 2010, and in the European Union (EU), Norway, Iceland and Liechtenstein in 2013 for the treatment of advanced, castration-resistant (hormone-refractory) prostate cancer (PCa). 

But for the majority of researchers, the journey to develop a safe and effective cancer vaccine has proven to be frustratingly slow and challenging. In the wake of many disappointments, new vaccine approaches have been employed and resulted in several candidates reaching late-stage development.

Dendritic cell-based vaccines
Hot in the pipeline are dendritic cell-based vaccines, such as sipuleucel-T, which use the patient's own dendritic cells isolated from blood by a procedure called leukapheresis. The dendritic cells are cultured in vitro, and loaded with prostatic acid phosphatase (PSA) in combination with the adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) to enhance antigen presentation and stimulate a strong immune response. When re-introduced to the patient, the dendritic cells instruct other immune system cells to attack and destroy the cancer cells.

Some researchers hope a cocktail of cancer-associated antigens will provide a potent immune response

Other dendritic-cell vaccines use the patient's whole tumour RNA to mount an immune response against the complete antigenic repertoire of the individual's tumour. 

AGS 003 consists of dendritic cells that have been loaded with whole tumour RNA using Argos Therapeutics' proprietary Arcelis Personalised Immunotherapy Platform. A phase III trial of the vaccine in combination with sunitinib is ongoing in the US, Canada, the EU and Israel, in patients with metastatic renal cell carcinoma. 

Another example is Northwest Biotherapeutics' brain cancer vaccine (DCVax), which is in global phase 3 development for the treatment of glioblastoma multiforme, an aggressive form of brain cancer. The vaccine consists of dendritic cells pulsed with a tumour cell lysate prepared from surgically resected tumour tissue using the company's DCVax vaccine technology. 

SOTIO is developing a similar vaccine (DCVAC/PCa), which consists of dendritic cells pulsed with dead PCa cells. The vaccine is designed to be used in combination with first-line chemotherapy for the treatment of metastatic, hormone-refractory PCa. 

Tumour-cell vaccines 
Another treatment option is tumour-cell vaccines, which contain tumour cells obtained from the patient following surgery. These vaccines are intended to prevent disease recurrence in patients who have received prior treatment. 

AVAX Technologies is developing a melanoma vaccine, which is marketed as MVax in Switzerland for the post-surgical treatment of stage III and IV malignant melanoma. The vaccine was developed using AC Vaccine technology licensed from the Thomas Jefferson University in the US, and consists of tumour cells conjugated to dinitrophenyl, a highly immunogenic hapten. 

Another tumour-cell vaccine is Vaccinogen's colorectal cancer vaccine (OncoVAX), which aims to prevent tumour recurrence, and is awaiting approval in Switzerland. The vaccine is made of autologous tumour cells combined with a proprietary formulation of the Bacillus Calmette-Guérin adjuvant, and is designed for intradermal administration four times over a six-month period following surgery. In a phase III trial, the vaccine significantly reduced the risk of tumour recurrence by 61 per cent in patients with stage II colon cancer. 

A further late-stage candidate is dasiprotimut T (BiovaxID), which is being developed by Biovest International and the US National Cancer Institute (NCI) to extend disease-free survival in patients who have received chemotherapy for late-stage indolent follicular lymphoma. Phase III development of the vaccine in combination with GM-CSF has been completed, and the company is planning to file for approval in the US, EU and Canada.

Meanwhile, rather than using autologous cells, Aduro BioTech is developing cancer vaccines that consist of allogeneic cells to enable efficient, large-scale production. The cells are genetically modified to secrete GM-CSF for an enhanced immune response. Phase III development is underway in the US for the treatment of PCa.

Antigen vaccines
Perhaps a more cost-effective option lies in developing vaccines using common cancer-associated antigens (CAAs), which in theory could treat a large number of tumours. 

Tecemotide (Oncothyreon, Merck KGaA, Merck Serono) consists of mucin-1 (MUC-1), a cell surface glycoprotein that is over-expressed and structurally different in approximately 90 per cent of solid tumours and haematological malignancies (including breast, prostate, colorectal and ovarian tumours, and multiple myeloma). Tecemotide is in global phase III development for treatment of stage III unresectable non-small cell lung cancer (NSCLC).

GlaxoSmithKline's astuprotimut-R is also in global phase III development for the treatment of NSCLC and malignant melanoma, and consists of a recombinant melanoma-associated antigen 3 (MAGE-A3) that is expressed on many solid tumours and haematological malignancies. The vaccine is combined with a proprietary immunoadjuvant, and is intended to reduce the risk of tumour recurrence following surgery. 

Other vaccines in late-stage development include KAEL-GemVax's tertomotide, Galena Biopharma's nelipepimut S, Celldex's rindopepimut and Optimer Biotechnology's OBI 822, which consist of the common tumour antigens telomerase, HER-2/neu or globo-H.

Further vaccines are designed to mount an immune response against hormones that are required by tumours for cell growth and survival. Cancer Advances is developing a polyclonal antibody stimulator, which consists of a diphtheria toxoid carrier protein and a synthetic peptide similar to a portion of the gastrin 17 hormone contained in a liquid suspension vehicle. The vaccine prevents the gastrin 17 hormone acting as a growth factor for a number of gastrointestinal malignancies, and is in phase III development in the US and Europe for the treatment of gastric cancer and pancreatic cancer. 

Some researchers have adopted a 'the more, the merrier' mentality, and mixed a cocktail of CAAs into one vaccine for a potent immune response. 

GreenPeptide and its licensee FUJIFILM are developing a vaccine for HLA-A2-positive advanced cancer, ITK 1, which consists of twelve different CAAs. The treatment is optimised for each individual by only selecting 'high-response' peptides with the intention of stimulating a more potent immune response, compared with single antigen vaccines. Phase III development is ongoing in patients with chemo-refractory, hormone-refractory PCa in Japan. 

Similarly, Immatics Biotechnologies is developing IMA 901, which consists of ten antigens that are expressed by the majority of renal cancers. Another late-stage candidate is Polynoma's malignant melanoma vaccine, POL 103A, which is prepared from pooled antigens from three proprietary melanoma cell lines. The phase III registrational MAVIS trial is underway in the US, which is assessing the ability of POL 103A to prevent relapse in patients with stage IIb, IIc and III melanoma. 

Other therapeutic cancer vaccines
Some therapeutic vaccines use anti-idiotypic monoclonal antibodies, which are unique in the sense that they are able to act as antigens. One such vaccine is racotumomab, which is marketed as Vaxira in Argentina and Cuba for the treatment of late-stage NSCLC. The vaccine was developed by a public-private consortium founded by joint venture company Recombio, and resembles glycolylated gangliosides (Neu-glycolyl-GM3) located on the membrane of melanoma, breast and lung cancer cells. 

Another anti-idiotypic vaccine is Menarini's abagovomab, which mimics an epitope on the tumour-associated antigen, CA125. The vaccine is in phase III development for the treatment of epithelial ovarian, fallopian tube and peritoneal cancers in the US and EU.

Viral-vector based vaccines are also in the works. BN ImmunoTherapeutics and the US NCI are developing a viral-vector based vaccine, rilimogene galvacirepvec-rilimogene glafolivec (PROSTVAC), which is in phase III development for the treatment of metastatic, hormone-refractory PCa. The vaccine has two components: a recombinant vaccinia vector for the primary vaccination, and a recombinant fowlpox vector for multiple booster vaccinations. Both vectors contain the transgenes for PSA and multiple T-cell co-stimulatory molecules. 

But ultimately, though Dendreon's success has led the way, successful development of a therapeutic cancer vaccine is still dependent on addressing the issues of tumour heterogeneity, immune system evasion and lack of immunogenicity that bedevil most researchers.

Article by
Jennifer Prossler

Adis International (Springer Healthcare), using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Daniela Ranzani on +39 02 423 4562 or Email: Daniela.Ranzani@ springer.com

24th February 2014

From: Research

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