Recognizing the Disruptive Potential of Cancer Immunotherapy

This article from MDB Communications discusses ten cancer vaccine programs in mid- and late-stage development with important catalysts expected during the balance of 2013 and into 2014. The article also highlights how several of these newer products seem to work better and address the limitations of prior cancer vaccine approaches. The 11-page report is available electronically as a PDF file.  To view/download a complimentary copy of the report, please click here.

Rethinking Immunotherapy for Brain Tumors

As highlighted in our prior articles, growing evidence indicates that the field of cancer immunotherapy, broadly defined as including passive immunization, active immunization, and immunostimulation, is coming of age.  More than 40 unique active cancer immunotherapies are currently being tested in over 60 clinical trials, with nearly a dozen readouts from randomized Phase 2 or Phase 3 trials expected during the next 12-months.

Immunotherapy for cancers of the central nervous system [CNS], however, continues to be met with skepticism.  Amongst the reasons for such incredulity are concerns that the nervous system may be immunologically privileged[i] and the presence of the blood-brain barrier, which only allows entry of select immune cells from the peripheral blood into the brain.  However, all of these premises have now been substantially discounted and tumors in the CNS should not be considered “off-limits” to immunotherapy[ii].

In addition, recent observations of how the CNS system behaves and interacts with the immune system have shed some light into the potential role of immunotherapy in the treatment of brain cancer.  Consider the following facts:

  • People with impaired immune systems have an increased risk of developing CNS lymphomas[iii], suggesting that the immune system has a role in the manifestation of tumors in these patients.  People with compromised immune systems include organ transplantation patients taking immunosuppressive drugs, HIV patients, and cancer patients being treated with chemotherapy, which can weaken immune functionality.
  • Bridget McCarthy, Ph.D. of the University of Illinois at Chicago found that patients with gliomas were significantly less likely to report having any type of allergy.  In fact, patients who had more types of allergies, such as seasonal, medication, pet, or food allergies, had up to a 64% reduction in risk of developing glioma[iv]. This suggests a relationship between immunological activity and potential protection from the development of CNS tumors.
  • Neurologists and neurosurgeons provide anecdotal reports that glioma patients who experience postoperative infections near the tumor bed seem to do better than the average patient similar to the observations made over a century ago by Coley[v].  This suggests that exogenous factors, such as infections, may result in the activation of the immune system and improve the odds of combating CNS tumors.

Collectively, these observations suggest that proper activation of the immune system in patients with CNS tumors could be beneficial.  Accordingly, we sought to review select companies advancing immunotherapy approaches for brain tumors [see Table 1].

Table 1. Eight Companies with Immunotherapy Approaches for Brain Tumors

Company Market Cap Clinical Pipeline Corporate Partner(s) Stage(s) [# of programs]
Agenus, Inc. (AGEN) $62M Prophage Series*, QS-21 Stimulon® adjuvant, HerpV GlaxoSmithKline (GSK), Johnson & Johnson (JNJ), ChemRar, and Integrated Biotherapeutics Phase III [4], Phase II [10], Phase 1 [1]
Celldex Therapeutics (CLDX) $202M Rindopepimut [CDX-110]; CDX-011, CDX-1401, CDX-1127, CDX-301 n/a Phase III [1], Phase II [3], Phase I [2]
Immatics Biotechnologies (private) n/a IMA-901, IMA-910, IMA-950 n/a Phase III [1], Phase II [1], Phase I [1]
ImmunoCellular Therapeutics (IMUC) $72M ICT-107 n/a Phase II [1]
Innocell Corp (031390.KQ) n/a Immuncell-LC** n/a Phase III [1]
Northwest Biotherapeutics (NWBO) $31M DCVax® n/a Phase II [1]
Oncovir, Inc. (private) n/a Hiltonol (Poly-ICLC) n/a Phase II [2], Phase I [2]
TVAX Biomedical (private, IPO planned) ~$80M at IPO TV1-Brain-1, TV1-Kidney-1 n/a Phase II [1]

* Marketed in Russia as Oncophage® for intermediate-risk renal cell carcinoma, ** Marketed in Korea for hepatocellular carcinoma

About Glioma

Glioma is the most common form of primary brain tumors.  They are solid tumors that arise from glial cells, which help support the function of the neurons.  Glial cells include astrocytes, oligodendrocytes and ependymal cells.  The overgrowth of abnormal glial cells may begin in the brain or spinal cord tissues.

Gliomas can be divided into two categories: low-grade, which are not benign but have a better prognosis, or high-grade, which are malignant and often cause death within months, despite surgery or treatment with chemotherapy or radiation, according to the National Cancer Institute.

Glioblastoma multiforme [GBM], a high-grade glioma, is the most common and aggressive primary brain tumor.  In contrast, tumors originating from astrocytes [astrocytoma] range from Grade 1, which are very benign, to Grade 4, which is the same as a glioblastoma.

Amenable to Immunotherapy

Beyond recent observations suggesting a role for immunotherapy in treating brain tumors, several other factors make glioma an ideal indication for immunotherapy.  First, glioma rarely metastasizes beyond the brain, resulting in a low overall tumor burden within the body.  Second, while the blood-brain barrier is thought to restrict entry of immune cells from the peripheral blood into the brain of healthy individuals, glioma disrupts the blood brain barrier, allowing for the freer trafficking of T-cells.  Finally, glioma tumor tissue, especially in patients who are newly diagnosed, is amenable to surgical resection therefore lowering tumor burden at time of vaccination [minimal residual disease].  Studying cancer immunotherapy in settings with bulky or metastatic disease might help explain some of the past failures, as the immune system may not be able to thwart such extensive disease.  Accordingly, minimal disease settings are ideal for cancer immunotherapy.

Strategies for Immunotherapy in Glioma

In general, two categories of immunotherapeutic approaches for the treatment of glioma are currently being pursued: cell-free vaccines and cell-based vaccines.

Cell-free vaccines

Cell-free vaccines may contain heat-shock protein-peptide (HSP) complexes derived from the patient’s tumor following surgery [autologous] or incorporate one or more defined tumor peptides plus an adjuvant [non-autologous].  The following companies are advancing cell-free vaccines:

  • Agenus, Inc.: autologous HSPs that elicit both CD4+ and CD8+ T-cell response and also innate response
  • Celldex Therapeutics: a single EGFRvIII peptide
  • Immatics Biotechnologies: 11 tumor associated, synthetic peptides

Cell-based vaccines

Cell-based vaccines often incorporate dendritic cells [DC] pulsed with defined tumor peptides, tumor cell lysate, brain tumor stem cell mRNA.  Alternatively, some cell-based vaccines consist of adoptive lymphocyte infusion and/or irradiated tumor cells.  The following companies are advancing cell-based vaccines:

  • ImmunoCellular Therapeutics: DCs pulsed with shared HLA-A1/A2 tumor peptides
  • Innocell Corp: adaptive transfer of cytokine-induced T-cells/NK cells
  • Northwest Biotherapeutics: DCs pulsed with tumor lysate
  • Oncovir, Inc.: a-type 1 polarized DCs pulsed with defined HLA-A2 peptides plus poly-ICLC adjuvant
  • TVAX Biomedical: whole cell vaccination plus adoptive transfer of lymphocytes

To date, commercializing cell-based vaccines has been challenging.  For example, Dendreon’s (DNDN) Provenge® [sipuleucel-T] for prostate cancer is a cell-based vaccine that fell short of Wall Street analyst expectations during the first full year of commercial launch.  Provenge and other DC-based cancer vaccines require leukopherisis to acquire a patient’s dendritic cells.  This process adds to the overall cost of producing the vaccine and makes the logistics somewhat complicated.  In contrast, cell-free vaccines can be derived from synthetic peptides or from the patient’s tumor following standard surgical resection, making the treatment process more user friendly from both a physician and patient perspective.

Clinical Development of Immunotherapy for GBM

The current standard of care for GBM, based on a prospective, randomized controlled trial published in 2005, involves maximal surgical resection with adjuvant radiation therapy and temozolomide[vi].  Despite this therapeutic regimen, median overall survival is between 14.6 and 19.6 months for newly diagnosed patients and between 6 and 9 months for recurrent GBM[vii],[viii].

While immunotherapy approaches for GBM would be expected to perform better in the newly diagnosed setting, some companies first established proof-of-concept for their product candidates in the relapsed setting.  Due to the shorter expected survival, these Phase I/II studies may be faster and less expensive.  If hints of efficacy are observed in the relapsed disease setting, the product candidates can then be explored in the newly diagnosed setting.

In view of differences among histologies, ages, trial designs, and the small number of patients with immunotherapy studies published to date in the recurrent GBM setting, comparing and contrasting the findings is difficult [see Table 2].  For example, in the largest single study [56 patients] from the Catholic University of Leuven, the median age was the lowest [45 years] due to the inclusion of children above the age of seven.  In addition, some of the studies included patients that were not diagnosed with GBM, such as astrocytomas that can vary in grade.

In contrast to the results obtained with current standard of care, several of the studies with cancer vaccines for recurrent GBM have demonstrated a median overall survival greater than nine months.  Some of these trials where immune responses have been measured, such as the Prophage G-200 [HSPPC-96] trial, have shown impressive immunological activity post vaccination.  More impressive and certainly more relevant, these responses have also been measurable locally at the tumor site, which suggests such a response may be more meaningful from the perspective of effectively combating the disease.

Table 2. Recurrent GBM Vaccine Data

Company/

Institution

Product/

Reference

Clinical Stage

# Patients w/ GBM

Median Age

Overall Survival in Months

Agenus, Inc. Prophage G-200 [HSPPC-96][ix] Phase II 33/33 53 [n=33] 11 [n=33]
Catholic University of Leuven, Belgium DC pulsed w/ tumor lysate [+/- booster of lysate without DC][x] Phase I/II 56/56 45 [n=56] 9.6 [n=56]
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, California DC pulsed w/ tumor lysate[xi] Phase II 21/32 54 [n=32] 13.4 [n=12] to 20 [n=9]
TVAX Biomedical TV1-Brain-1[xii] Phase I 16/19 50 [n=19] 12 [n=19]
Niigata University School of Medicine, Niigata, Japan DC pulsed w/ tumor lysate[xiii] Phase I/II 18/24 53 [n=18] 16 [n=18]
Oncovir/University of Pittsburgh a-type 1 polarized DCs pulsed w/ defined HLA-A2 peptides plus poly-ICLC adjuvant[xiv] Phase I/II 13/22 54 [n=13] 12 [n=13]

 

Several companies are also currently conducting immunotherapy trials in newly diagnosed GBM, with encouraging results presented to date, including Agenus [ClinicalTrials.gov: NCT00905060], Celldex Therapeutics [ClinicalTrials.gov: NCT01480479], Immatics [ClinicalTrials.gov: NCT01222221], ImmunoCellular [ClinicalTrials.gov: NCT01280552], Innocell Corporation [ClinicalTrials.gov: NCT00807027], and Northwest Biotherapeutics [ClinicalTrials.gov: NCT00045968].

An important future direction for the successful treatment of these very difficult tumors may involve the combination of immunotherapeutic agents with other synergistic treatments.  Such approaches could simultaneously address the immunosuppressive, angiogenic, invasive, and hypoxic nature of GBM.  In this regard, combination approaches with Avastin® [bevacizumab] and other potentially synergistic agents would make imminent sense to pursue.

Note: For further information on this topic, click here to view a replay of the plenary session “Advances in immunotherapy for glioma” by Andrew T. Parsa, M.D., Ph.D., University of California, San Francisco, from MD Becker Partners’ 2nd Annual “Cancer Immunotherapy: A Long-Awaited Reality” Conference held October 6, 2011.

References


[i] Medawar PB.  Immunity to homologous grafted skin: the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol. 1948 Feb;29(1):58-69.

[ii] Heimberger AB, Sampson JH.  Immunotherapy coming of age: What will it take to make it standard of care for glioblastoma?  Neuro Oncol. 2011 Jan;13(1):3-13. Epub 2010 Dec 10.

[iii] Guinto G, Félix I, Aréchiga N, Arteaga V, Kovacs K. Primary central nervous system lymphomas in immunocompetent patients.  Histol Histopathol. 2004 Jul;19(3):963-72.

[iv] McCarthy BJ, Rankin K, Il’yasova D, Erdal S, Vick N, Ali-Osman F, Bigner DD, Davis F. Assessment of type of allergy and antihistamine use in the development of glioma.  Cancer Epidemiol Biomarkers Prev. 2011 Feb;20(2):370-8.

[v] Nauts HC, McLaren JR. Coley toxins – the first century.  Adv Exp Med Biol. 1990;267:483-500.

[vi] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.  N Engl J Med. 2005 Mar 10;352(10):987-96.

[vii] Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, Fisher J; NABTT CNS Consortium.  Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States.  Clin Cancer Res. 2010 Apr 15;16(8):2443-9. Epub 2010 Apr 6.

[viii] Caroli M, Locatelli M, Campanella R, Motta F, Mora A, Prada F, Borsa S, Martinelli-Boneschi F, Saladino A, Gaini SM.  Temozolomide in glioblastoma: results of administration at first relapse and in newly diagnosed cases. Is still proposable an alternative schedule to concomitant protocol?  J Neurooncol. 2007 Aug;84(1):71-7. Epub 2007 Mar 15.

[ix] A. Parsa, C. Crane, S. Han, V. Kivett, A. Fedoroff, N. A. Butowski, S. M. Chang, J. L. Clarke, M. S. Berger, M. McDermott, M. Aghi, C. Yanes, M. Prados, A. E. Sloan, J. N. Bruce.  Autologous heat shock protein vaccine (HSPPC-96) for patients with recurrent glioblastoma (GBM): Results of a phase II multicenter clinical trial with immunological assessments.  J Clin Oncol 29: 2011 (suppl; abstr 2565)

[x] De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, Sciot R, Wilms G, Demaerel P, Warmuth-Metz M, Soerensen N, Wolff JE, Wagner S, Kaempgen E, Van Gool SW.  Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme.  Clin Cancer Res. 2008 May 15;14(10):3098-104.

[xi] Wheeler CJ, Black KL, Liu G, Mazer M, Zhang XX, Pepkowitz S, Goldfinger D, Ng H, Irvin D, Yu JS.  Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.  Cancer Res. 2008 Jul 15;68(14):5955-64.

[xii] Sloan AE, Dansey R, Zamorano L, Barger G, Hamm C, Diaz F, Baynes R, Wood G.  Adoptive immunotherapy in patients with recurrent malignant glioma: preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes.  Neurosurg Focus. 2000 Dec 15;9(6):e9.

[xiii] Yamanaka R, Homma J, Yajima N, Tsuchiya N, Sano M, Kobayashi T, Yoshida S, Abe T, Narita M, Takahashi M, Tanaka R.  Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial.  Clin Cancer Res. 2005 Jun 1;11(11):4160-7.

[xiv] Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, Mintz AH, Engh JA, Bartlett DL, Brown CK, Zeh H, Holtzman MP, Reinhart TA, Whiteside TL, Butterfield LH, Hamilton RL, Potter DM, Pollack IF, Salazar AM, Lieberman FS.  Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma.  J Clin Oncol. 2011 Jan 20;29(3):330-6. Epub 2010 Dec 13.

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.

History

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.

Conclusion

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.

References


[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 http://www.who.int/vaccines-documents/DocsPDF06/863.pdf

[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.

Similarities Between Two Immunotherapies in Cancer

Approval of Bristol-Myers Squibb’s (BMY) Yervoy® [ipilimumab] for melanoma in March 2011 marked the second victory for the field of immunotherapy in oncology within a year, with the first being the U.S. Food and Drug Administration [FDA] approval of Dendreon Corporation’s (DNDN) Provenge® [sipuleucel-T] for metastatic castrate-resistant prostate cancer [CRPC] in April 2010.  Ipilimumab was the first immune check point molecule and sipuleucel-T was the first active immunotherapy for cancer to demonstrate improved survival in randomized Phase 3 trials.  Both were published in the prestigious New England Journal of Medicine within one month of each other.

The similarities don’t end there, as both ipilimumab and sipuleucel-T have reignited enthusiasm for the field of active immunotherapy.  Accordingly, the purpose of this article is to highlight some of the other parallels between these two innovative agents.

Both Studied in Prostate Cancer

While ipilimumab was recently approved for the treatment of melanoma, the product has also been extensively studied in prostate cancer.  In fact, there are eight clinical studies with ipilimumab in prostate cancer according to ClinicalTrials.gov, including five that are currently active or recruiting.

One particular prostate cancer study made headlines in June 2009 when investigators at the Mayo Clinic reported in the online research magazine Discovery’s Edge that the combination of a single dose of ipilimumab [3 mg/kg] with androgen ablation therapy dramatically reduced the tumor size in two patients, making surgery possible for both patients whose prostate cancer had been previously considered inoperable. The controversial results from a handful of patients were met with skepticism and the complete Phase 2 results with 108 patients with advanced prostate cancer were later reported at the American Society of Clinical Oncology [ASCO] 2010 Genitourinary Cancers Symposium [abstract #168].  According to the ASCO abstract, patients treated with androgen ablation either alone or in combination with ipilimumab demonstrated a greater than 97% decline in testosterone levels, underscoring the possibility that the tumor reductions in a few patients could have been associated with androgen ablation.  Patients treated with ipilimumab, however, were more likely to have undetectable prostate specific antigen [PSA] by three months [55% vs. 38%].

A Phase 3 trial with ipilimumab following radiation therapy in patients with CRPC that have received prior treatment with docetaxel is ongoing [ClinicalTrials.gov identifier NCT00861614].

Two is Better than One

As the first two active immunotherapies approved for the treatment of cancer, it wouldn’t be surprising to see the products studied in combination in prostate cancer – especially in view of the fact that ipilimumab has already been studied in this disease.  Sipuleucel-T may help build an effective immune response to kill tumor cells, while ipilimumab may stimulate the immune system through T-cell activation and proliferation and stop tumor cells from growing.  Accordingly, giving vaccine therapy together with ipilimumab may be an effective treatment for prostate cancer.  Interestingly, the only such combination study listed on ClinicalTrials.gov relates to a completed Phase 1 trial with ipilimumab in combination with Bavarian Nordic’s (BAVA.CO) Prostvac®, an “off-the-shelf” therapeutic cancer vaccine moving into pivotal Phase 3 clinical development [ClinicalTrials.gov identifier NCT00124670].

Pricing Controversy

Both Dendreon’s sipuleucel-T and Bristol-Myers’ ipilimumab have been criticized as overly expensive new therapies.

The cost of sipuleucel-T is approximately $93,000 for a course of treatment, which consists of three infusions at two-week intervals.  In view of the fact that the product has been demonstrated to extend median survival by 4.1 months, this translates into an average cost of $23,000 per month of added survival.

In comparison, Taxotere® [docetaxel] by Sanofi-aventis (SNY) is indicated for the treatment of CRPC and is administered every 3 weeks for 10 cycles.  Assuming an average monthly cost of $4,000 for docetaxel [source: Cancer Res 2009;69(24 Suppl):Abstract nr 1076], this is an approximate total cost of $40,000 per patient.  In the pivotal TAX 327 study, median survival for prostate cancer patients receiving docetaxel was 18.9 months versus 16.5 months in the control arm, which results in an average cost of $16,666 per month of added survival or about 28% less than sipuleucel-T.  Updated survival analysis of the TAX 327 study demonstrates a 2.9-month survival advantage, which lowers the average cost to $13,793 per month of added survival or about 40% less than sipuleucel-T.  Unlike sipuleucel-T, however, treating common adverse reactions with docetaxel, such as infections, neutropenia, anemia, nausea, diarrhea, and others, increases the total cost of therapy – and more importantly negatively impacts the patient’s quality of life.  As such, the pricing of sipuleucel-T doesn’t appear completely out of line.

According to the prescribing information, ipilimumab is administered intravenously [3 mg/kg] over 90 minutes every 3 weeks for a total of four doses.  Bristol-Myers is pricing each dose at $30,000, which translates into a total cost of $120,000 for a full course of therapy.  In the pivotal ‘020 study, median survival for melanoma patients receiving ipilimumab was 10.1 months versus 6.4 months in the control arm.  The average cost per month of added survival is approximately $32,432, which is 41% higher than the only other active immunotherapy for cancer, sipuleucel-T.

However, on March 21, 2011, Bristol-Myers announced that the ‘024 study [ClinicalTrials.gov identifier NCT00324155] met its primary endpoint of overall survival.  Minimal details were provided, but an abstract of the ‘024 data is expected to be submitted to ASCO for potential presentation at the Annual Meeting in June 2011.  The ‘024 study is in patients with untreated Stage III [unresectable] or IV melanoma receiving dacarbazine plus 10 mg/kg ipilimumab versus dacarbazine with placebo.  If the median survival for patients in the ipilimumab arm is 5.2 months or greater than the placebo arm [versus 3.7 month difference in the ‘020 study], then the pricing of ipilimumab per month of added survival would be comparable to sipuleucel-T.

Prostate and Melanoma Highly Competitive

Melanoma and prostate cancer are the two most crowded clinical development segments within the active immunotherapy field.  As such, both ipilimumab and sipuleucel-T may face competition from other active immunotherapies in the near future.  In addition, the products may soon encounter small molecule rivals.

For example, Johnson & Johnson’s (JNJ) abiraterone acetate significantly improved overall survival for patients with metastatic advanced prostate cancer.  Based on the positive Phase 3 results, the company has filed marketing applications for abiraterone acetate with regulatory authorities worldwide for the treatment of metastatic advanced prostate cancer that has developed resistance to conventional hormonal therapies. Not far behind, Medivation, Inc. (MDVN) is evaluating its MDV3100 product candidate in collaboration with Astellas Pharma, Inc. (ALPMY.PK).  The Phase 3 AFFIRM trial with MDV3100 has completed enrollment of men with advanced prostate cancer who were previously treated with docetaxel-based chemotherapy and the Phase 3 PREVAIL trial with MDV3100 is currently enrolling men who have not yet received chemotherapy

In addition, Plexxikon, Inc. [being acquired by Daiichi Sankyo Company, Limited] and co-development partner Roche Holding (ROG.VX) are advancing PLX4032, an oral drug candidate that targets the oncogenic BRAF mutation present in about half of melanoma cancers and about eight percent of all solid tumors.  Interim data from a Phase 3 controlled study of PLX4032 in previously untreated metastatic melanoma patients with the BRAF mutation met both co-primary endpoints.  Patients treated with PLX4032 had improved overall survival (OS) and improved progression-free survival (PFS) compared to patients treated with dacarbazine, the current standard of care.  A New Drug Application [NDA] for PLX4032 is expected in 2011.

Some new agents might actually be synergistic with active immunotherapies instead of representing potential competition.  This was a central theme at the recent Cancer Immunotherapy Consortium’s 2011 Scientific Colloquium titled “Schedule and Dose for Combination Therapy.”

Summary

Both ipilimumab and sipuleucel-T represent important clinical advances for the field of active immunotherapy in oncology and for patients with melanoma and prostate cancer, respectively.  Further, with nearly 50 clinical programs currently underway, including nearly a dozen that are in pivotal Phase 3 development, we expect to see five active cancer immunotherapies approved by 2015.  Beyond these clinical accomplishments, however, industry observers will be closely monitoring the commercial success of these innovative agents in view of the product pricing, supply constraints, and competitive dynamics identified to date.

Ipilimumab Approval Highlights Immunotherapy Renaissance

On Friday, March 25, 2011, the U.S. Food and Drug Administration [FDA] approved Yervoy® [ipilimumab] by Bristol-Myers Squibb (BMY) for the treatment of patients with late-stage [metastatic] melanoma. With the news, ipilimumab becomes the eleventh monoclonal antibody [mAb] approved for the treatment of cancer.  The first mAb approved for cancer treatment was Biogen Idec, Inc’s (BIIB) Rituxan® [rituximab] back in November 1997 [click here to see graph of mAb approvals].

Approval of ipilimumab is the second victory for the field of active immunotherapy in oncology within a year.   On April 29, 2010, the FDA approved the very first active immunotherapy for the treatment of cancer – Dendreon Corporation’s (DNDN) Provenge® [sipuleucel-T] for metastatic castrate-resistant prostate cancer [CRPC].  The fact that two active immunotherapies have demonstrated improved survival in randomized Phase 3 trials and subsequently been approved by the FDA has reignited enthusiasm for the field of active immunotherapy, which has experienced nearly a dozen failures in Phase 3 clinical trials.

A Long Time in the Making

The idea to stimulate one’s own immune system to treat cancer dates back to 1891 when William Coley, Professor of Clinical Surgery at Cornell University, noticed the curative effect of an accidental bacterial infection in a patient with inoperable sarcoma.  It would be 119 years since Dr. Coley’s discovery before the FDA approved the first active immunotherapy for the treatment of cancer.

As the scientific understanding of the immune system has significantly increased since Dr. Coley’s time, scientists and physicians developed successful immune system related strategies to fight cancer, viral infection and autoimmune diseases.  Today, mAbs are among the most successful modern immunotherapies and provide clinical benefit to a vast array of diseases – with three blockbuster mAbs generating approximately $17 billion in sales in 2009.

Melanoma Losing Streak

In addition to helping renew interest in the field of active immunotherapy, the FDA’s approval of ipilimumab provides a much-needed boost to companies developing product candidates for melanoma.  Among the eleven Phase 3 failures with active immunotherapies for the treatment of cancer, more than one-third of them have occurred in melanoma [see Table 1].

Table 1. Select Active Immunotherapy Failures in Phase 3 Trials

Company Product Candidate Description Result
CancerVax Canvaxin Allogeneic, whole cell tumor derived No improvement in overall survival
Progenics Pharmaceuticals, Inc. (PGNX) GMK vaccine GM2 ganglioside coupled with KLH and formulated with QS-21 No improvement in relapse-free or overall survival
Corixa Melacine Allogeneic, Mel S/Mel D cell lines No improvement in relapse-free or overall survival
Agenus, Inc. (AGEN), formerly Antigenics Oncophage® Autologous, whole cell tumor derived heat shock proteins No improvement in overall survival

Crowded Market

While ipilimumab is the first new drug approved for the treatment of melanoma in 13 years, there are four competitive active immunotherapy programs in Phase 3 development [see Table 2].  In fact, melanoma is second only to prostate cancer as the most crowded clinical development segment within the active immunotherapy field.

Table 2. Select Phase 3 Active Immunotherapy Product Candidates in Melanoma

Company Product Disease(s) Type Stage
Amgen (AMGN) through the acquisition of BioVex Group OncoVEX[GM-CSF] Melanoma [unresectable Stage III b-c and Stage IV M1a-c], and head & neck Allogeneic, oncolytic herpes simplex virus encoding GM-CSF for direct injection into lesions Phase 3 ongoing
AVAX Technologies (AVXT.PK) MVAX Melanoma [Stage IV], and ovarian Autologous, whole cell, hapten modified SPA approved for Phase 3
GlaxoSmithKline plc (GSK) MAGE-A3 ASCI Melanoma [metastatic – stage III-IVa progressive],  and NSCLC Allogeneic, peptide Phase 3 ongoing
Vical, Inc. (VICL) and AnGes Allovectin-7® Melanoma [1st line Stage III and IV] Allogeneic, DNA plasmid/lipid complex Phase 3 ongoing

Five by 2015

As highlighted in our firm’s April 2010 report titled “Cancer Vaccine Therapies: Failures and Future Opportunities,” there are a number of additional catalysts that could ignite further interest in the field of active immunotherapy for cancer.  Nearly 50 clinical programs are currently underway, including nearly a dozen that are in pivotal Phase 3 development.

Using the history of passive immunotherapy development as a guide, it would not be surprising to see five active cancer immunotherapies approved within five years, which leads to our “5 x 2015” projection.  With the approvals of both sipuleucel-T and ipilimumab in hand, the next three may come from the following list of Phase 3 product candidates [in alphabetical order]:

  • Amgen (AMGN), OncoVEX[GM-CSF], melanoma and head & neck
  • AVAX Technologies (AVXT.PK), MVAX, melanoma
  • Bavarian Nordic (BAVA.CO), Prostvac®, prostate cancer
  • Biovest International (OTCQB: BVTI), BiovaxID®, NHL
  • Cel-Sci (CVM), multikine, head & neck
  • Celldex Therapeutics (CLDX), rindopepimut/CDX-110, glioblastoma
  • GlaxoSmithKline (GSK), MAGE-A3 ASCI, NSCLC and melanoma
  • Novarx (private), Lucanix™/belagenpumatucel-L, NSCLC
  • Oncothyreon (ONTY)/Merck KGaA, Stimuvax®/BLP25 liposome vaccine, NSCLC
  • Oxford BioMedica plc (OXB.L), Trovax®, renal cell
  • Transgene (TNG.PA)/Novartis (NVS), TG4010/MVA-MUC1-IL2, NSCLC
  • Vical (VICL)/AnGes, Allovectin-7®, melanoma

Five Key Factors Weighing on Dendreon

Shares of Dendreon Corporation (DNDN) have declined significantly from an all-time high of $57.67 in late April 2010 when the company received U.S. Food and Drug Administration [FDA] approval for Provenge® [sipuleucel-T], the first active immunotherapy approved for the treatment of cancer in the U.S.  Today, shares of Dendreon traded as low as $28.01, down more than 50% from their high, prompting us to briefly review some of the key factors weighing on the company at this time.

Product pricing and reimbursement

The cost of Provenge has been set at $93,000 for a course of treatment, which consists of three infusions at approximately two-week intervals.  In view of the fact that Provenge has been demonstrated to extend survival by 4.1 months, this translates into an average cost of $23,000 per month of added survival.

In comparison, Taxotere® [docetaxel] by Sanofi-aventis (SNY) is indicated for the treatment of patients with androgen independent [hormone refractory] metastatic prostate cancer and administered every 3 weeks for 10 cycles.  Assuming an average monthly cost of $4,000 for Taxotere [source: Cancer Res 2009;69(24 Suppl):Abstract nr 1076], this is an approximate total cost of $40,000 per patient. In the pivotal TAX 327 study, median survival for prostate cancer patients receiving Taxotere was 18.9 months versus 16.5 months in the control arm, which results in an average cost of $16,666 per month of added survival.  Unlike Provenge, however, treating common adverse reactions with Taxotere, such as infections, neutropenia, anemia, nausea, diarrhea, and others, increases the total cost of therapy – so the pricing of Provenge doesn’t appear completely out of line. [note: updated survival analysis of the TAX 327 study demonstrates a 2.9 month survival advantage, which lowers the average cost to $13,793 per month of added survival with Taxotere.  Source: Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 242-245.]

Nonetheless, the Centers for Medicare and Medicaid Services [CMS] has initiated a National Coverage Analysis [NCA] of Provenge. In CMS’s announcement of the NCA, CMS is requesting public comments on the effects of Provenge on health outcomes in patients with prostate cancer. While the news doesn’t reflect a change in Medicare coverage policy or impact existing coverage decisions and a decision isn’t expected for a year, it does highlight sensitivity on the part of payors over the pricing of certain cancer treatments.

Supply constraints

Dendreon is making Provenge available through approximately 50 centers, all of which were approved Provenge clinical trial sites, and expects to increase capacity over the next year.  The increased capacity will be a result of the anticipated licensure of its expanded New Jersey, Georgia and California facilities in mid-2011.

In the short term, however, Dendreon officials have indicated that the company will only be able to supply 2,000 treatments to patients.  At a cost of $93,000 per treatment, this limits potential sales to approximately $186 million.

According to a June 28 article by Bloomberg reporter Tom Randall, Dendreon’s Chief Operating Officer Hans Bishop indicated that facilities will be able to churn out medicine each year valued at between $1.25 billion and $2.5 billion by the end of 2011.

Competitive landscape

In early April 2010, we published a 150-page industry report titled “Cancer Vaccine Therapies: Failures and Future Opportunities,” which included an overview of the cancer immunotherapy market, interviews with several key opinion leaders, profiles of nearly 40 companies, and a discussion of the scientific, clinical, and commercial considerations for the major industry participants.

In the report, we highlighted the fact that numerous active immunotherapies are in late-stage clinical development for prostate cancer.  In fact, nine product candidates are in clinical trials for the treatment of prostate cancer, representing the largest therapeutic area within the active immunotherapy market.  Beyond competition from other active immunotherapies, however, Provenge could also face competition from small molecule products.

For example, Johnson & Johnson (JNJ) acquired Cougar Biotechnology, Inc. for approximately $1.0 billion in cash in 2009.  Cougar Biotechnology’s oncology portfolio included abiraterone acetate [CB7630], an orally active acetate salt of the steroidal compound abiraterone.  Abiraterone acetate, which can suppress testosterone production by both the testes and the adrenals to castrate-range levels, is currently in two Phase III clinical trials for the treatment of prostate cancer according to ClinicalTrials.gov [Trial identifier numbers NCT00638690 and NCT00887198].  Both studies list a primary completion date of mid-2011.

Insider sales

Trading conducted by corporate officers, key employees, directors, or significant shareholders must be reported to the Securities and Exchange Commission [SEC], usually within a few business days of the trade.  Some investors follow the activity of insiders, believing that they might have better insights into the health of a corporation and that their trades convey important information – although this isn’t always the case.

In this regard, according to a Form 4 filed with the SEC, Dendreon’s Chief Executive Officer [CEO] beneficially owned 555,211 shares of the company’s common stock as of April 29, 2010 – the day Provenge was approved by the FDA.  The CEO sold more than half of those shares at prices ranging from $51 to $54.70, reducing his beneficial holdings to 224,359 the next day.  Other insiders also sold during the period.

Priced for perfection

Recall that Eli Lilly & Co. (LLY) purchased ImClone Systems for $6.5 billion back in 2008.  ImClone’s only product – Erbitux® [cetuximab] – had generated annual sales of approximately $1.3 billion in 2007.  Therefore, ImClone was valued at a 5x multiple to prior year sales.

At its 52-week high, Dendreon had a market capitalization of approximately $7.8 billion.  At a 5x multiple, this would imply an annual revenue run rate of $1.56 billion, which is consistent with the company’s planned manufacturing capacity by the end of 2011 and many analyst projections over the coming years.

But Dendreon isn’t generating $1.56 billion in annual sales yet and concerns over pricing, reimbursement, and competition, combined with insider selling, help explain the decrease in market valuation since the approval of Provenge.

Cancer Immunotherapy to Take Center Stage at ASCO

In early April 2010, we published a 150-page industry report titled “Cancer Vaccine Therapies: Failures and Future Opportunities,” which included an overview of the cancer immunotherapy market, interviews with several key opinion leaders, profiles of nearly 40 companies, and a discussion of the scientific, clinical, and commercial considerations for the major industry participants.   An executive summary of the report can be found by clicking here.

Some of the key messages from the report include the following:

  • Reminiscent of monoclonal antibodies in the late 1990’s, the field of active immunotherapy is poised for dramatic growth in the coming years
  • Nearly 50 clinical programs involving active immunotherapies for the treatment of cancer are currently underway, including nearly a dozen that are in pivotal Phase III development with several biologic license application [BLA] submissions planned in 2010
  • Using the history of passive immunotherapy [monoclonal antibodies] as a guide, we expect five active cancer immunotherapies approved within the next five years that will revolutionize the treatment of cancer
  • Beyond Dendreon Corporation’s (DNDN) Provenge®, there are a number of additional catalysts in 2010 that could ignite further interest in the field of cancer immunotherapy

A list of potential catalysts for cancer vaccine companies in 2010 was included in our initial report, such as the presentation of new clinical data during the American Society for Clinical Oncology [ASCO] annual meeting being held June 4-8, 2010. However, following a review of the abstracts published online, we identified three additional vaccine companies worth watching at ASCO.

Interestingly, the three companies span the largest segments of cancer vaccine development – allogeneic peptides [17 programs in development], gene transfer [15 programs in development], and autologous dendritic cell approaches [9 programs in development]. The first two approaches represent “off the shelf” cancer vaccines, while the latter is a “personalized” approach. To date, the only active immunotherapy approved for the treatment of cancer in the US is Dendreon’s Provenge, which is an autologous approach.

Bavarian Nordic A/S (BAVA.CO)

Bavarian Nordic, who’s stock price reached a multi-year high following approval of Dendreon’s Provenge, is developing Prostvac™ [also known as PSA-TRICOM], under a license from the National Cancer Institute [NCI]. Prostvac is a vector-based vaccine that targets prostate-specific antigen [PSA] and includes the transgenes for three human costimulatory molecules to enhance T-cell activation.  Following the recent publication of encouraging Phase II results and receipt of Fast Track designation from the FDA, Bavarian Nordic is planning to initiate a pivotal Phase III prostate cancer trial in 2010.

At ASCO, Bavarian Nordic is scheduled to present “Overall survival [OS] analysis of a phase l trial of a vector-based vaccine [PSA-TRICOM] and ipilimumab [Ipi] in the treatment of metastatic castration-resistant prostate cancer [mCRPC]” during the Developmental Therapeutics – Clinical Pharmacology and Immunotherapy General Poster Session held Monday, June 7, 8:00am to 12:00pm in S Hall A2. Separately, the company announced an investor and analyst briefing to be held in conjunction with ASCO on Saturday, June 5, 2010, in Chicago, IL.

Generex Biotechnology Corporation (GNBT)

While Canada’s Generex is perhaps better known for its $250 million lawsuit against TheStreet.com and senior columnist Adam Feuerstein regarding two articles expressing doubts about the company’s oral insulin spray for the treatment of diabetes, its wholly owned subsidiary [Antigen Express, Inc.] is scheduled to present “Effect of a novel II-key hybrid HER2/neu peptide (AE37) vaccine with GM-CSF as compared to GM-CSF alone on levels of regulatory T-cell (Treg) populations” during the Developmental Therapeutics – Clinical Pharmacology and Immunotherapy General Poster Session held Monday June 7, 8:00am to 12:00pm in S Hall A2.

HER-2 is a growth factor receptor that is over-expressed by approximately 20-30% of patients with localized breast cancer and is the target for Herceptin® [trastuzumab] by the Roche Group (RHHBY). However, Generex isn’t the only company targeting HER-2/neu for the treatment of breast cancer. Other cancer vaccine developers working with the target include Dendreon, Bavarian Nordic, Apthera, Inc., and others.

Prima Biomed Ltd. (PRR.AX)

Similar to the concept behind Dendreon’s Provenge, Prima Biomed is developing an autologous dendritic cell vaccine for the treatment of cancer. The company’s lead product candidate is called CVac™, which incorporates the MUC-1 antigen that is overexpressed in cancer, including epithelial ovarian carcinoma. According to the company, prior phase I and II studies conducted in Australia in heavily pretreated, advanced disease patients showed minimal toxicities and prolonged disease stabilization.

Prima Biomed is scheduled to present “A randomized, open-label phase IIb study of maintenance therapy with a MUC-1 dendritic cell vaccine in patients with epithelial ovarian cancer in first or second remission” during the Trials in Progress Poster Session held Monday, June 7, from 8:00am to 12:00pm in S Hall A2.

Consistent with ASCO’s policies, we won’t report on research information represented by the aforementioned abstracts until the information is publicly released in conjunction with the annual meeting. Suffice it to say that we believe active immunotherapy for the treatment of cancer will take center stage at this year’s meeting.