Critical Success Factors For The Immunotherapy Race

by: Andrew J. Norris

Previously we covered differing approaches taken by emerging and innovative publicly traded companies in the cancer vaccine space. This article will probe another aspect of performance that is more practical: critical success factors for dominating companies that will emerge from this race. Although not the only criteria that are determinant, they are some of the most important in this space. Four criteria will be discussed, which include aspects surrounding the technology used to enhance immune response to the drug (the type of adjuvant/delivery system employed), the breadth of antigens targeted by the drug, the targeting of cancer stem cells, and the use of cost-effective technology so as to avoid some of the earlier pitfalls in reimbursement, logistics, and expense of development.

1. Adjuvant or delivery system for robust immune response: Of principal importance in this race is understanding that clinical outcomes are related to immune response generated by these drugs. As a result, there are various approaches to address this challenge. Adjuvants, by definition, are pharmacological agents added to a drug in order to increase or aid its effectiveness. In this particular example an adjuvant is an agent that increases the immunological antigenic response. This is not only something that improves the drug action but is an essential factor because as mentioned, survival benefits are highly correlated with the immune response generated by the drug. A review of the criteria and the various approaches are described below.

a. Dendritic cells: (Dendreon (DNDN), ImmunoCellular Therapeutics (IMUC), Northwest Biotherapeutics (OTCQB:NWBO)). Dendritic Cells (DCS) are immune cells forming an important part of the human immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, DCs function as antigen-presenting cells where they act as messengers between the innate and adaptive parts of the immune system with the potential to either stimulate or inhibit immune responses. Thus, DCs interact with the immune systems T-cells and B cells to initiate and shape (direct) the adaptive immune response. A DC tumor vaccine is defined as DCs loaded with, for example, tumor associated antigen(s). Upon administration into patients, DC tumor vaccines are designed to induce an antigen-specific T-cell response against the tumor. Very small numbers of activated DCs are actually highly efficient at generating immune responses against endogenous tumors as is the same for viruses, other and various pathogens. DC manufacturing technology has evolved significantly over the last twenty years. Today's latest technology (third generation DCs) are what is being used by IMUC while the first generation activated monocytes is being employed by DNDN, which consequently, are less potent antigen presenting cells. Immunologists consider third generation DCs as the gold standard for immunostimulation from which other adjuvants are compared. A summary of adjuvants used is shown in Table I.

Table I: Adjuvant technologies used in cancer vaccines.

b. GM-CSF plus peptides: (Galena Biopharma (GALE), Generex Biotechnology (OTCPK:GNBT), Immatics). Granulocyte-macrophage colony-stimulating factor, often abbreviated as GM-CSF, is a protein secreted by immune cells (specifically: macrophages, T-cells, mast cells, endothelial cells among others). GM-CSF is often referred to as a cytokine which functions as a white blood cell growth factor and is also used as a medication to stimulate the production of white blood cells following chemotherapy. Thus, it is part of the immune/inflammatory cascade, by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fighting infection. It is this agent that when combined with an antigen will potentiate or enhance the immune response against that antigen which in this particular case, the immune reaction against a cancer target. GM-CSF serves to enhance an immune response but directing the immune reaction to a tumor target is typically performed by the use of short peptides (protein fragments) from a tumor specific cell surface protein/receptor. One of our previous examples of this was Galena Biopharma cancer vaccine NeuVax™ comprised of peptide (9 amino acids) from the extracellular part of the HER2 protein (E75 peptide) and combined with GM-CSF. This gives the drug its combined immunomodulation and tumor targeting activity. Upon injection, the E75 peptide plus GM-CSF vaccine is designed to induce a specific cytotoxic T-lymphocyte response against HER2/neu-expressing tumor cell types which is the case in HER+ breast cancer.

c. Liposomes/QS-21: (GlaxoSmithKline (GSK), Agenus (AGEN)). QS-21 is actually a plant carbohydrate derived product (from the Soap bark tree (Quillaja saponaria; Chile) that enhances the ability of the immune system to respond to vaccine antigens. This agent has been tested in a carrier agent (liposomes) as an Immunologic adjuvant in many vaccines such as for HIV, malaria and in this case, cancer to improve their efficacy where it has already been tested in several thousand patients. Examples of this are GSK vaccine candidate MAGE-A3 for selected patients with non-small cell lung cancer, and melanoma. Also, Agenus Inc. Prophage Series G-100 for newly diagnosed glioma and Prophage Series G-200 for recurrent glioma which are both in Phase II trials.

d. CpG: (Pfizer (PFE)). The full name of this technology is CpG oligodeoxynucleotides (or sometimes referred to as CpG ODN) which is basically short synthetic DNA molecules that act as a danger signal to human immune system. The CpG pattern is recognized by B cells and dendritic cells in humans and thus makes an excellent aduvant/immunostimulant. This technology is employed in the drug by Pfizer CPG-7909 (PF-3512676, ProMune®), which activates a receptor (toll-like receptor-9), hence promoting activation of human dendritic cells and B cells. Subsequently, this induces potent innate immune responses among vaccine adjuvants deployed in the treatment of cancers, infections, asthma and allergy. Among all the non-cellular adjuvants, CpG is probably one of the most potent adjuvants.

2. Larger antigen repertoire for multiple disease indications. Among the four topics discussed, this is one of the most meaningful as far as recurrence of the disease. It is now understood that within a cancer cell population, the antigenic profile can change quite rapidly and even within differing sections of a metastatic tumor, antigens present on one may not be on another. This has very significant implications for future drug design where multiple targets will likely become the norm in immunotherapeutic treatment plans. Cancer is clearly defined as a moving target and for vaccine technology the capacity to include multiple antigen strategies in development phase is certainly much more achievable than conventional chemotherapeutics. Secondly, the ability to include multiple antigenic epitopes allows a wider range of disease indications to be achievable with the same drug, hence wider market opportunity for that drug. Although the approval process has historically favored the one drug-one target approach, for oncology, this will become less and less the norm. See Table II for companies that are targeting multiple different antigens either by using the patient's own tumor (NWBO, Amgen (AMGN)) or synthetic antigens custom built for specific tumor (NYSEMKT:IMUC).

3. Targeting cancer stem cells: New evidence is showing cancer stem cells (CSCs) are actually one of the most significant underlying causes of tumor recurrence in addition to metastasis. For traditional chemotherapeutic treatment regimens, these issues are highly problematic because these drugs act on a select target relevant to cancer cells; however a key factor in the length of the clinical responses is that the cells develop a resistance to treatment over time. Evidence regarding the reason for this acquired resistance is now seen to be related to the presence of a small minority of cells in the tumor called cancer stem cells (CSCs) which are not addressed by conventional chemotherapeutics today. These CSCs are often highly resistant to existing cancer therapies including targeted drugs, chemo- and radiation therapy and end up repopulating the cells lost within the tumor after treatment.

The benefit of drugs specifically targeting CSCs is to provide a truly effective treatment that can create a lasting clinical response. In order to do this, it is now apparent that it is vital to develop drugs that can also target and kill CSCs. A major factor that has prevented the discovery of drugs targeting CSCs is that isolated CSCs rapidly differentiate in culture, yielding the non-CSCs that represent the majority of cells in tumors. This has now been recognized and is being pursued by key innovators in the field. Cancers originate in tissue progenitor or stem cells through dysregulation of the self-renewal process throughout tumorigenesis. CSCs drive tumor growth and simply said, without killing CSCs, it is like spraying for weeds without killing the roots. The weeds (tumors) will come back. CSCs will be an important target over the next decade for new drug development. In the category of cancer vaccines, IMUC is currently the only company targeting these cancer stem cells giving them a significant leg-up in long term.

4. Cost Effective Technologies: Although the majority of drug development costs are represented by the approval process it goes without saying that drug manufacture costs have a significant impact on accessibility (insurance reimbursement and access). The technologies mentioned above 1(b), 1(c) and 1(d) above, are all off-the-shelf materials that are inexpensive to prepare compared to dendritic cells. Part of the Challenges Of Cell-Based Cancer Immunotherapy is that there are extra costs in the manufacture of the product that can reduce the company's profit margins. Logistical issues and cost of goods sold are primarily responsible for the lower margins experienced from Dendron's Provenge® since product launch two years ago. Newer technologies are overcoming these limitations (NWBO and IMUC) as they drive down production per dose costs closer to other off-the-shelf solutions.

Click to enlarge image.

Table II: Technology profile for the various products with ( - ) being weak and (XXX) very strong.

In summary, these key criteria, although clearly not all that is required for success within this complex game, may provide helpful insight into the space and define early rules of the game. Although clinical outcomes will determine the success, eventually the factors discussed here will play a key role in ensuring the clinical success for the next generation of immunotherapy products.

With respect to new products and developments, I will be attending the annual meeting of American Society of Clinical Oncology (ASCO) in Chicago from June 1-4, where these companies and more will be presenting. Please follow me here on Seeking Alpha and at my website for blogs and live updates during ASCO 2012.

Disclosure: I am long IMUC.