Adjuvants May Hold Key to Unlocking Cancer Immunotherapy Revolution

Adjuvants May Hold Key to Unlocking Cancer Immunotherapy Revolution

The FDA approval of sipuleucel-T [Provenge®], a patient-specific immunotherapy for androgen independent prostate cancer developed by Dendreon Corporation (DNDN), and ipilimumab [Yervoy®], the first immune check point molecule for melanoma by Bristol-Myers Squibb (BMY), has renewed interest in the concept of immunotherapy as an approach to cancer treatment. Often overlooked, however, adjuvants can be an essential part of an effective vaccine and could help advance the field even further.

Adjuvants are substances that can:

  • Accelerate the generation of robust, longer lasting immune responses
  • Generate antibodies with increased avidity and neutralization capacity
  • Enhance immune responses in individuals with weakened immune systems
  • Reduce the amount of antigen and number of doses needed; reducing the cost of vaccination programs
  • Activate the cellular arm of the adaptive response, specifically T helper type 1 and cytotoxic T cell responses

For next generation cancer vaccines that require T cell immunity or a broader range of antibody response, adjuvants are playing an essential and central role[1]. For example, GlaxoSmithKline’s (GSK) melanoma antigen epitope-3 [MAGE-A3] antigen-specific cancer immunotherapeutic [ASCI] uses the company’s AS15 adjuvant system[2], which incorporates three different adjuvants [QS-21, MPL, and CpG] and is currently in pivotal Phase III trials for both non-small cell lung cancer [NSCLC] and melanoma with data expected in 2012.


During the last 80 years many adjuvants have been used in experimental settings, but due to various shortcomings of most of them only three have made it into regular clinical usage[3] – largely for infectious diseases.  Of the three adjuvants, only two have been used in vaccines licensed by the US Food and Drug Administration [FDA].

Alum (1930s)

For infectious disease vaccines, the most commonly used adjuvants are aluminum salt based [aluminum phosphate and aluminum hydroxide; alum], which are safe and effective for antibody induction.  Alum is a component of many licensed human vaccines, including diphtheria-pertussis-tetanus [DPT], diphtheria-tetanus [DT], DT combined with Hepatitis B virus [HBV], Haemophilus influenza B or inactivated polio virus [IPV], hepatitis A [HAV], Streptococcus pneumonia, meningococcal, and human papilloma virus [HPV].

MF59™ (1997)

MF59 is a potent vaccine adjuvant that has been licensed for more than 13 years for use in an influenza vaccine focused on elderly subjects [Fluad®] by Novartis (NVS)[4].  It consists of an oil-in-water nano-emulsion composed of shark oil [squalene] and has been licensed in Europe for use in influenza vaccines, but not in the US.

MPL® (2009)

MPL [monophosphoryl lipid A] is a derivative of bacterial endotoxin and a potent immunostimulant.  MPL was the second FDA licensed adjuvant molecule and is used in Cervarix® by GlaxoSmithKline, which is a prophylactic vaccine against HPV types 16 and 18.  GlaxoSmithKline obtained MPL through the $300 million acquisition of Corixa Corporation in 2005.  MPL is also the first and only toll-like receptor [TLR] ligand approved in a human vaccine.  TLRs are a class of proteins that play a key role in the innate immune system[5].

Few adjuvants approved

Adjuvants do not receive FDA approval as stand-alone products, but rather as part of a registered vaccine adjuvant–antigen combination[6].  The fact that safety regulations are often much more stringent with vaccines, as they are prophylactic and the main targets are often pediatric patients, partly explains why there are so few adjuvants approved to date[7].

Several recent developments have favorably altered the landscape for adjuvant development.  First, GSK’s Cervarix vaccine received approval in 2009 and contained the first adjuvant [MPL] licensed by the FDA since the approval of Alum back in the 1930s.  The second development has been FDA approval of sipuleucel-T [Provenge®] by Dendreon and ipilimumab [Yervoy®] by Bristol-Myers Squibb, which has renewed interest in the concept of immunotherapy as an approach to cancer treatment.  In the cancer setting, adjuvants are being tested as part of a therapeutic vaccine as opposed to being use as a prophylactic vaccine, which may result in a shorter duration of exposure and reduced safety concerns.  Third, if an influenza pandemic were to occur, such as the 2009-10 H1N1 pandemic, the potential vaccine supply would fall several billion doses short of the amount needed to provide protection to the global population[8]. The antigen-sparing effect of adjuvants could allow for expansion of vaccine supply to meet the necessary global demands during a pandemic, as evidenced by supporting grants from the Biomedical Advanced Research and Development Authority [BARDA], part of the US Department of Health and Human Services.

Investigational adjuvants

Several companies are developing promising new candidates that may finally adjunct or displace aluminum substances as a popular adjuvant:

Agenus (AGEN)

Agenus Inc. (AGEN) is developing QS-21, a saponin extracted from the bark of the Quillaja saponaria tree, also known as the soap bark tree or Soapbark, an evergreen tree native to warm temperate central Chile.  Quillaia raw material has been used for decades as an ingredient to create the foaming in beverages such as root beer, low-alcohol beers and foaming carbonated beverages.  It has also been widely used as an adjuvant in veterinary vaccines.

QS-21 has extensive clinical experience with thousands of patients receiving vaccines containing QS-21 adjuvant.  Agenus has licensed QS-21 to various Big Pharma partners and today there are 15 vaccine candidates using QS-21 in clinical development for infectious diseases, oncology, and central nervous system disorders, including the following Phase III programs by GlaxoSmithKline that could address large markets:

  • MAGE-A3 ASCI vaccine candidate, which is being studied in the largest-ever trial in the adjuvant treatment of NSCLC and also in Phase III trials for melanoma, with data expected in 2012
  • Mosquirix (RTS,S), the world’s most advanced malaria vaccine candidate, with Phase III data expected by the end of 2011

Agenus is entitled to receive milestone payments and royalties from corporate partners that have licensed QS-21.

Antigen Express, Inc., a wholly-owned subsidiary of Generex Biotechnology Corporation (GNBT)

Antigen Express is advancing its proprietary Ii-Key hybrid technology.  Ii-Key modification entails attaching a four-amino acid peptide [LRMK] to virtually any antigen and results in increased stimulation of CD4+ helper T cells and a more robust specific response to the antigen.  Using this technology platform, Antigen Express is building a deep pipeline of therapeutics aimed at a variety of major diseases, including cancer, infectious diseases and autoimmune-based syndromes.

The company’s lead product candidate using Ii-Key modification is AE37, a peptide vaccine derived from a fragment of the HER-2/neu protein, which is expressed in a variety of tumors including 75-80% of breast cancers as well as a high percentage of prostate, ovarian and other cancers[9].

A controlled, randomized, and single-blinded Phase II clinical study of AE37 in HER-2 expressing breast cancer patients is currently underway to establish clinical efficacy.  The study endpoint is a reduction in cancer relapse after two years compared to the current standard of care treatment.  There are currently over 200 patients enrolled in the study with either node positive or high-risk node-negative breast cancer.

Celldex Therapeutics (CLDX) and 3M Company (MMM)

3M Drug Delivery Systems has a portfolio of patent protected TLR agonists that have shown promise as vaccine adjuvants. The lead candidate, resiquimod [TLR7/8 agonist] has shown promising results in a number of animal models and has an extensive toxicology and clinical data package to support further development as a vaccine adjuvant.

Celldex Therapeutics entered into a non-exclusive clinical research collaboration with 3M Drug Delivery Systems to access resiquimod for clinical study with the company’s Antigen Presenting Cell [APC] Targeting Technology™ in exchange for an undisclosed licensing fee, milestones and royalties.  Celldex is developing CDX-1401, a fusion protein consisting of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC-205 linked to the NY-ESO-1 tumor antigen, which is currently in a Phase I/II trial in combination with immune stimulating agents [resiquimod and/or poly-ICLC] for advanced cancers of the bladder, breast, ovary, non-small cell lung cancer, myeloma, sarcoma or melanoma.

Colby Pharmaceutical Company (private) and Juvaris BioTherapeutics (private)

In September 2011, Juvaris BioTherapeutics, Inc. entered into an exclusive license agreement with Colby Pharmaceutical Company for the worldwide development and commercialization of Juvaris’ Cationic Lipid-DNA Complex [CLDC] technology and related JVRS-100 product candidate. Gene array studies with JVRS-100 show up-regulation of multiple immune response pathways compared to competing technologies. When combined with a vaccine antigen, JVRS-100 stimulates the adaptive immune response including specific antibodies and T-cell responses.

Idera Pharmaceuticals (IDRA)

Idera is developing numerous compounds that act as agonists for TLRs 3, 7, 8, or 9, which the company believes have the potential to be used as adjuvants in vaccines.  In preclinical animal models, Idera’s TLR agonists have shown adjuvant activity when combined with various types of antigens.

In December 2007, Idera entered into an exclusive, worldwide licensing and collaboration agreement with Merck KGaA for the research, development, and commercialization of Idera’s TLR9 agonists, including IMO-2055, for the treatment of cancer, excluding vaccines.  Merck KGaA refers to IMO-2055 as EMD 1201081.

Merck KGaA expects to complete an ongoing Phase 2 clinical trial of IMO-2055 in combination with cetuximab [Erbitux®] in second-line cetuximab-naïve patients with recurrent or metastatic squamous cell carcinoma of the head and neck [SCCHN].  However, based on increased incidence of neutropenia and electrolyte imbalances reported in its Phase 1 trial of IMO-2055 in combination with cisplatin/5-FU and cetuximab in patients with first-line SCCHN and subsequent re-evaluation of its clinical development program, in July 2011 Merck KGaA informed Idera that it will not conduct further clinical development of IMO-2055.

Immune Design Corporation (private)

Founded by the co-founder of Corixa Corporation, Immune Design Corporation is developing its proprietary adjuvant known as glucopyranosyl lipid A [GLA].  GLA is a novel, clinical-stage, human TLR-4 agonist, representing the next generation of MPL.  According to the company, GLA is unique because: it is a pure synthetic small molecule, straightforward to manufacture with excellent stability, rationally designed to optimally activate human TLR-4 receptors, induces Th1 CD4 helper cells and elicits broad humoral immunity and active in multiple formulations and compatible with most antigens.  GLA was also shown to be safe and well-tolerated in humans subjects in a Phase I clinical study in combination with the influenza virus vaccine Fluzone® by Sanofi Pasteur, the vaccines division of sanofi-aventis Group (SNY).  Immune Design Corporation is developing its own proprietary pipeline of vaccine candidates formulated with the GLA adjuvant for evaluation in further human clinical trials.

Vical Inc. (VICL)

Vical is developing Vaxfectin®, a novel proprietary cationic lipid-based formulation that has been shown to effectively enhance plasmid DNA-based [as well as protein- and peptide-based] vaccines. It is a commixture of a cationic lipid [GAP-DMORIE] and a neutral phospholipid [DPyPE] which, when combined in an aqueous vehicle, self-assemble to form liposomes.  In mechanism of action studies, Vaxfectin® has been shown to increase a number of cytokines and chemokines, while Toll-like receptor signaling was contributory.

Vical is developing several products that utilize Vaxfectin® as an adjuvant. These include CyMVectin™, the company’s prophylactic vaccine against cytomegalovirus [CMV] infection, and its pandemic influenza vaccines.


Beyond their established role in infectious diseases, adjuvants will also likely become important in cancer immunotherapy where they will be critical for targeting weakly immunogenic tumor antigens in order to overcome various tolerance mechanisms and facilitate induction of cytotoxic T lymphocytes.  Several promising new adjuvants are currently being developed that offer superior properties and a set of desired characteristics, with clinical data expected in the near future.

The topic of adjuvants in cancer immunotherapy will covered in an upcoming panel session at the second annual Cancer Immunotherapy: A Long-Awaited Reality conference being held in New York City on October 6, 2011.


[1] Adjuvants for cancer vaccines. Dubensky TW Jr, Reed SG. Semin Immunol. 2010 Jun;22(3):155-61. Epub 2010 May 21. Review.

[2] Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Garçon N, Van Mechelen M. Expert Rev Vaccines. 2011 Apr;10(4):471-86. Review.

[3] The ABC of clinical and experimental adjuvants–a brief overview. Brunner R, Jensen-Jarolim E, Pali-Schöll I. Immunol Lett. 2010 Jan 18;128(1):29-35. Epub 2009 Nov 4.

[4] MF59 adjuvant: the best insurance against influenza strain diversity. O’Hagan DT, Rappuoli R, De Gregorio E, Tsai T, Del Giudice G. Expert Rev Vaccines. 2011 Apr;10(4):447-62.

[5] Impaired TLR3/IFN-beta signaling in monocyte-derived dendritic cells from patients with acute-on-chronic hepatitis B liver failure: relevance to the severity of liver damage. Li N, Li Q, Qian Z, Zhang Y, Chen M, Shi G. Biochem Biophys Res Commun. 2009 Dec 18;390(3):630-5. Epub 2009 Oct 13.

[6] Adjuvants for malaria vaccines. Coler RN, Carter D, Friede M, Reed SG. Parasite Immunol. 2009 Sep;31(9):520-8. Review.

[7] Delivery Technologies for Biopharmaceuticals: Peptides, Proteins, Nucleic Acids and Vaccines edited by Lene Jorgensen and Hanne Mørck Nielsen

[8] Global pandemic influenza action plan to increase vaccine supply by the World Health Organization at

[9] AE37: a novel T-cell-eliciting vaccine for breast cancer. Sears AK, Perez SA, Clifton GT, Benavides LC, Gates JD, Clive KS, Holmes JP, Shumway NM, Van Echo DC, Carmichael MG, Ponniah S, Baxevanis CN, Mittendorf EA, Papamichail M, Peoples GE.

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