Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Monthly Archives: September 2012

Is Novartis building a viable business model for adoptive immunotherapy for cancer?


Tumor infiltrating lymphocytes (TILs) in a colorectal carcinoma. Source: Nephron.

On April 27, 2011 we published an article on this blog entitled “Adoptive immunotherapy for metastatic melanoma?” This blog post, which was in part based on an article in the April 2011 issue of The Scientist, described a treatment for metastatic melanoma known as adoptive cell transfer (ACT), or adoptive immunotherapy. ACT is the only type of therapy that has resulted in high percentages of durable compete responses in metastatic melanoma. A durable complete response, which is tantamount to a cure, is the real desire of every cancer patient, and of their loved ones, and of caring physicians who treat them.

In ACT, a physician/researcher extracts a patient’s antigen-specific immune cells, which are usually found in tumor tissue. Such cells are known as “tumor infiltrating lymphocytes” (TILs). He or she then expands the numbers of the antitumor T lymphocytes in cell culture, using the T-cell growth factor, IL-2. The physician/researcher then infuses the cells, plus IL-2, intravenously into the patient. The infused T cells traffic to tumors and can mediate their destruction. Prior to TIL infusion, the patient may have his or her immune system temporarily ablated via “preparative lymphodepletion” with chemotherapy and sometimes also total-body irradiation. The preparative lymphodepletion treatment is associated with enhanced persistence of the transferred TILs.

In a clinical study of ACT published in 2011, the treatment resulted in the disappearance of all tumors in 20/93 patients (21.5%) with advanced metastatic melanoma. For 19 of these 20 patients (95%), the complete responses have been durable and long-lasting, in some cases lasting for over 7 years. (See also the Faculty of 1000 evaluation.)

Research on the mechanistic basis of adoptive immunotherapy, as well as on means to improve ACT technologies, is ongoing, so there is the potential to improve the durable complete response rate further. We featured a December 2012 Nature cancer immunotherapy review article that included a discussion of ways to improve ACT in the 2011 end-of-year article on our Biopharmconsortium Blog.

Despite the fact that ACT is the only type of therapy that has resulted in high percentages of durable compete responses in metastatic melanoma, it is not widely available. ACT is only available in a small number of cancer canters worldwide, and there has been little commercial interest in developing ACT.

Adoptive immunotherapies are still considered experimental, are not FDA-approved, and are not covered by third party payers. Thus only a handful of locations can bear the financial burden of administering adoptive immunotherapy. If a cancer center has a cell production facility with the required staff, the cost of producing a single dose of T-cells for adoptive transfer is approximately $20,000. ACT treatment also entails factoring in the cost of hospitalization. However, most patients only require a single dose.

The cost of ACT is, however, much lower than a full course of other immunotherapies, such as the dendritic cell vaccine Provenge (which is not indicated for melanoma) or the immunotheraputic MAb drug ipilimumab, both of which cost approximately $120,000. The total cost of a 6-month treatment with the targeted kinase drug vemurafenib is $56,400. None of these treatments result in durable complete responses, except in a very small number of patients.

The main problem with increasing the availability of ACT is the lack of a viable business model for its commercialization. Adoptive immunotherapies lack a clearly defined claim to intellectual property (IP), since the patient’s own cells are not a “drug” to be patented. It would be difficult for a private company to pursue clinical trials for FDA approval and commercialization of ACT. To conduct such trials, a company would need to build a specialized cell processing and treatment facility, with a highly trained and competent staff. If the therapies cannot be protected as IP, and would therefore not be considered proprietary, it would not be worth the effort and expense to commercialize them.

The Novartis/Penn agreement

Now comes an agreement (announced on August 6, 2012) between Novartis and the University of Pennsylvania (Penn) aimed at commercializing adoptive cellular immunotherapy.

The agreement is based on one of the improvements to ACT discussed in the December 2011 Nature cancer immunotherapy review, in which autologous T cells isolated from patient blood (not from tumors) are engineered with retroviral vectors carrying chimeric antigen receptors (CARs). This technology allows physician researchers to extend ACT beyond patients from whom TILs can be isolated and expanded. It also enables them to extend ACT beyond melanoma to include other types of solid tumors and leukemias and lymphomas. Unlike TILs, CAR-bearing T cells do not recognize surface antigens on tumor cells [presented by major histocompatibility complex (MHC) proteins] via their T-cell receptors. They instead recognize surface proteins on tumor cells via the affinity domain on the engineered CAR. This also expands the kinds of tumor cells that can be recognized, as compared to TILs.

In the Penn studies, led by David L. Porter, M.D. at the Perelman School of Medicine of the University of Pennsylvania, the researchers used this technology to treat patients with chronic lymphocytic leukemia (CLL). They designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with the T cell costimulatory receptor CD137 and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. They used this vector to engineer autologous T cells, and infused the engineered cells into the patient after preparative lymphodepletion with chemotherapy. In a pilot study with one patient with refractory chronic lymphocytic leukemia (CLL), the infused cells exhibited in vivo expansion and anti-leukemia activity. The treatment resulted in complete remission, which was ongoing 10 months after initiation.

In a later study, the researchers treated three more patients with autologous engineered CAR T cells. The T cells expanded over 1000-fold in vivo, trafficked to bone marrow, and continued to express CARs at high levels for at least six months. The CAR T-cells showed anti-leukemia activity, with each engineered T cell eliminating approximately 1000 CLL cells. A CD19-specific immune response was demonstrated in the blood and bone marrow of two of three patients; these patents showed complete remission. Some of the cells in these patients persisted as memory CAR T cells and retained anti-CD19 effector activity. These results suggested that this technology has the potential to effectively treat B cell malignancies, and to induce durable complete remissions in at least a portion of patients.

As reported in August 2012, of the three patients who showed positive results with the anti-CD19 immunotherapy, two were still in complete remission over a year into the CART-19 trial, and the third patient maintained partial remission for more than seven months. An immune deficiency resulting from the treatment known as hypogammaglobulinemia, an expected chronic toxic effect of anti-B cell therapy, was corrected with infusions of intravenous immune globulin. Patients were also treated for symptoms associated with tumor lysis syndrome, an effect of tumor breakdown.

Under the agreement, Novartis acquired exclusive rights from Penn to CART-19, the investigational CAR immunotherapy that was the focus of the studies discussed earlier. The target of CART-19, CD19, is associated with several B-cell malignancies, including CLL, B-cell acute lymphocytic leukemia and diffuse large B-cell lymphoma. Novartis expects to initiate a Phase II clinical trial with CART-19 in collaboration with Penn during the fourth quarter of 2012.

To facilitate the discovery and development of additional types of CAR immunotherapy, Novartis and Penn will build the Center for Advanced Cellular Therapies (CACT) at Penn. This center will be established specifically to develop and manufacture adoptive T-cell immunotherapies under the research collaboration between Penn and Novartis.

Penn also granted Novartis an exclusive worldwide license to CARs developed through the collaboration for all indications, in addition to CART-19. In return, Novartis will provide an up-front payment, research funding, funding for the establishment of the CACT and milestone payments for the achievement of certain clinical, regulatory and commercial milestones as well as and royalties on any sales.

Business implications of the Novartis/Penn agreement

The feasibility of developing and commercializing CAR T-cell-based immunotherapy is based on the ability of Penn to patent and license its CAR technology. Such an approach in principle would apply to immunotherapies based on other types of engineered T cells, such as those engineered with retroviral vectors carrying cloned T-cell receptors, as discussed in the December 2011 Nature review article.

As discussed earlier, adoptive immunotherapies with engineered T cells would also address patients with a variety of types of cancer (not just melanoma) and from who TILs cannot be isolated. However, whether any therapies with engineered T cells can give the percentages of durable complete responses seen with TIL-based therapy of melanoma remains to be demonstrated in clinical trials.

The Novartis/Penn agreement represents an example of Novartis’ willingness to take risks, in order to “bring innovative therapies to patients”, as stated by Hervé Hoppenot, President, Novartis Oncology. Mark Fishman, President of the Novartis Institutes for BioMedical Research, sees cancer immunotherapy as “one of the exciting frontiers in cancer research,” and the CAR technology as showing “early promise as a new way for treating cancer.”

Novartis thus has not built a viable business model for TIL-based ACT. However, it is developing a parallel technology that is more protectable than TILs, which might result in bringing adoptive cellular immunotherapy to a much larger number of patients.

BiTE immunotherapy

Meanwhile another type of T-cell-based immunotherapy technology (also discussed in the Nature review) is now under development. This is bi-specific T-cell engager (BiTE) technology, originally developed by the German-American biotech company Micromet. Amgen acquired Micromet in April 2012, and is now developing the first BiTE agent, blinatumomab. Blinatumomab is a bispecific MAb that binds to CD19 on target B-cell malignancies and to CD3 (an invariant component of the T-cell receptor) on T cells. This results in the activation of the T cell to exert cytotoxic activity on the target cell. BiTE immunotherapy does not require isolation and culture of autologous T cells, and BITE technology and therapeutics derived from it are patentable as with other drugs.

In May 2012, Amgen reported that blinatumomab treatment gave a high rate (72 percent) of complete responses in a Phase 2 study in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL). The rate of remission seen in this trial was a great improvement over the current standard of care. However, no durable complete responses were seen; median survival was 9 months.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Alzheimer’s disease–where do we go from here?


New Alzheimer’s disease model, the CVN mouse

Our August 19, 2012 and our August 28, 2012 articles on this blog focused on the latest developments in Alzheimer’s disease (AD) drug development. To summarize the conclusions of the articles:

  • The results of a new genetic study by DeCode Genetics and its collaborators strongly support the amyloid hypothesis of AD, and especially the hypothesis that reducing the β-cleavage of APP [e.g., by use of an inhibitor of β-secretase (also known as the β-site APP cleaving enzyme 1, or BACE1)] may protect against the disease.
  • Nevertheless, in Phase 3 trials of two anti-amyloid monoclonal antibody (MAb) drugs in patients with mild to moderate AD–Pfizer/Janssen’s bapineuzumab (often called “bapi” for short) and Lilly’s solanezumab–the drugs failed their primary cognitive and functional endpoints.
  • Roche/Genentech, as well as two academic consortia, have begun clinical trials of anti-amyloid MAb drugs in asymptomatic patients with mutations that predispose them to develop AD, or in asymptomatic patients with amyloid accumulation. These studies are based on the hypothesis that the reason for the failure of anti-amyloid MAb drugs in clinical trials has been that the patients being treated had suffered extensive, irreversible brain damage. Treating patients at a much earlier stage of disease with these agents might therefore be expected to be more successful.

Analyses of the data from the Phase 3 studies of both bapi and solanezumab will be presented in scientific meetings in October 2012. An academic research consortium will present its independent analysis of the data from the EXPEDITION studies of solanezumab at the American Neurological Association (ANA) meeting in Boston on October 8, 2012, and at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in Monte Carlo, Monaco, on October 30, 2012.

According to a September 11, 2012 news article in Drug Discovery & Development, researchers who conducted the Phase 3 trials of bapi found evidence that the drug stabilized amyloid plaque in the brain and may have ameliorated further nerve damage in patients treated with the drug. This finding is among the results to be presented in the October meetings.

Development of BACE1 inhibitors

Strictly speaking, the results of the DeCode Genetics study most strongly support the development of BACE1 inhibitors. In our August 28, 2012 article, we link to a 2010 review that includes a discussion of companies developing BACE1 inhibitors. However, we also note that the development of BACE1 inhibitors has been elusive. This is because of medicinal chemistry considerations. Specifically, it has been difficult to design a specific, high-affinity inhibitor of the BACE1 active site that can cross the blood-brain barrier and which has good drug-like ADME (absorption, distribution, metabolism and excretion) properties. Nevertheless, recently progress has been made in developing such compounds, and several companies are developing BACE1 inhibitors and have entered them into early-stage clinical trials.

Among the companies developing BACE1 inhibitors, as listed in a recent post on Derek Lowe’s In The Pipeline blog are CoMentis/Astellas, Merck, Lilly, and Takeda.

Satori Pharmaceuticals was developing γ-secretase inhibitors, but ran into safety problems

Developing γ-secretase inhibitors has been abandoned by the vast majority of companies, because of the essential role of these enzymes in the Notch pathway and other pathways involved in normal physiology. As a result, development of γ-secretase inhibitors for AD has not progressed beyond the preclinical stage.

Nevertheless, Satori Pharmaceuticals, a Cambridge, MA venture capital-backed biotech company, had been actively involved in developing γ-secretase inhibitors. Satori’s γ-secretase inhibitors were based on a proprietary scaffold derived from a compound isolated from the black cohosh plant (Actaea racemosa). The company utilized modern synthetic and medicinal chemistry to derive compounds based on this scaffold that they believed was suitable for long-term oral therapy for AD in humans. Satori’s lead compound, SPI-1865, was a potent γ-secretase modulator that decreased levels of the amyloidogenic Aβ42 peptide as well as Aβ38, increased levels of Aβ37 and Aβ39, but did not affect Aβ40. Researchers believe that decreasing Aβ42 levels in favor of shorter, less amyloidgenic A-beta forms is beneficial in treatment of AD. SPI-1865 was also selective for Aβ42 lowering over the inhibition of Notch processing, and appeared to be free of any other off-target activities.

In animal models [e.g., wild type mice and rats, and transgenic mice (Tg2576) that overexpress APP and thus have high levels of Aβ peptides] orally-administered SPI-1865 has been found to lower brain Aβ42. SPI-1865 has good brain penetration in these models, and a long half-life that should permit once a day dosing in humans.

SPI-1865 was in the preclinical stage. Satori planned to file an Investigational New Drug (IND) Application with the FDA in late 2012 with the goal of enabling initial human testing to begin in the early part of 2013.

However, in late 2012, a study in monkeys showed that Satori’s lead compound–as well as its backup compounds–disrupted adrenal function. This adverse effect was completely unexpected, and unrelated to the gamma secretase target.  As of May 30, 2013, Satori closed its doors.

Meanwhile, other companies, including Envivo Pharmaceuticals (Watertown, MA), Bristol-Myers Squibb, and Eisai continue with their R&D efforts in gamma secretase modulators for treatment of AD.

A new mouse model for AD

As Derek Lowe says in an August 31, 2012 post on “In the Pipeline” with respect to Lilly’s AD drugs, anti-amyloid MAbs, BACE1 inhibitors, and γ-secretase inhibitors are “some of the best ideas that anyone has for Alzheimer’s therapy”. Given the APP processing pathway as illustrated in the figure at the top of our August 28, 2012 article, these are the “sensible” and “logical” alternatives.

Nevertheless, there is the nagging feeling among many AD researchers that we do not understand the causes of AD, especially sporadic AD, which represents around 95% of all cases of the disease. Sporadic AD occurs in aging individuals who have normal genes for the components of the APP processing pathway. Not only do we not understand the pathobiology of sporadic AD, but we have little understanding of the normal physiological function of APP and of APP processing. Processes that may be involved in the initiation of sporadic AD may include not only those involved in Aβ production, but also those involved in Aβ clearance.

An important tool in understanding the pathobiology of AD, and potentially in developing novel therapies for the disease, would be an animal model that recapitulates the human disease as closely as possible. We published an article on AD mouse models that were designed to more closely recapitulate human AD than the most commonly used models in the September 15, 2004 issue of Genetic Engineering News. However, since the publication of our article, Carol A Colton, Ph.D. (Duke University Medical Center, Durham, NC) and her colleagues have published on their research aimed at producing an even better mouse model, known as the CVN mouse. They published their research in two articles, one in PNAS in 2006 and the other in the Journal of Neuroscience in 2008.

Charles River Laboratories (CRL) (Wilmington, MA) now offers the CVN mouse to researchers who might wish to employ it in their AD research. CRL has also recently produced a webinar (with the participation of Dr. Colton) on the CVN mouse, entitled “CVN Mouse: A More Translatable Alzheimer’s Efficacy Model”. You may access this webinar by registering at

Genome-wide association studies (GWAS) in humans, as well as various functional studies, have implicated variants in genes involved in inflammation and immune responses in susceptibility to late-onset, sporadic AD in humans. The Colton group, noting that commonly-used mouse models of AD recapitulated human disease very poorly, looked for differences between mice and humans in innate immunity. The biggest difference they found was that expression of nitric oxide synthase 2 (NOS2) the inducible form of nitric oxide synthase, is high in mice and low in humans. NOS2 is an enzyme that produces nitric oxide (NO), a highly reactive oxidant that can serve in signal transduction, neurotransmission and in cell killing by macrophages. Microglia, the macrophages of the brain, express NOS2 and NO. The Colton group has been studying the role of microglia and oxidants and antioxidants in microglia that can produce oxidative stress in the brain in normal aging and in AD.

Because of the striking difference in NOS2 expression between mice and humans, the Colton group created a transgenic mouse AD model by crossing mice that  expressed a mutant form of human APP known as APPSwDI (APP Swedish Dutch Iowa) with NOS2 knockout (NOS2 -/-) mice. The APPSwDI transgenic mouse, a well-characterized standard AD mouse model, was chosen because it expresses low levels of APP and high levels of Aβ peptides in the brain. The APPSwDI/NOS2 -/- mouse is the CVN mouse that is available from CRL.

Unlike APPSwDI mice and other standard AD mouse models, the CVN mouse recapitulates many features of human AD as the animals age, including AD-like amyloid pathology (starting at 6 weeks of age, which is early), perivascular deposition of amyloid, AD-like tau pathology (including aggregated hyperphosphoryated tau), AD-like neuronal loss, and reduction in interneuron numbers (including NPY interneurons). Age-related cognitive (learning and memory) loss (as assessed by the radial arm water maze test) was also seen. The researchers also saw increases in immune activation and inflammation (e.g., microglial activation) over the course of the disease; this appeared to be dependent on increases in Aβ and in tau.

The researchers also used the mouse to study changes in immune-related proteins over the course of the disease. Several protein that are encoded by genes that have been associated with sporadic AD via GWAS change over time in this mouse model, including APOE (which has been known to be important in AD for a long time) and BIN1. Other proteins that change over the course of disease include the complement component C1QB, and the centrosomal protein ninein. Immune activation genes such as those that encode IL-1α and TGF-β also show changes over the course of disease in these mice. The Colton group will soon publish their work on changes in these proteins and genes in the CVN mouse in a peer-reviewed journal.

In summary, the CVN mouse more faithfully models AD-like progression than other mouse models that have been used to study AD, including those that have been used in preclinical studies of such failed drug candidates as solanezumab, bapineuzumab, Flurizan (tarenflurbil), and Alzhemed (3-amino-1-propanesulfonic acid). It also allows researchers to study the role of genes and proteins such as those identified in GWAS studies in AD, and especially in sporadic AD. (However since the CVN mouse expresses a mutant form of APP, it can not be used to study all aspects of the pathophysiology of sporadic AD, especially the initiation of the disease process.) The CVN mouse can also be used in drug discovery and preclinical studies.

One example of such drug discovery studies is being carried out by the Colton group. They have recently been studying small APOE mimetic peptides in CVN mice. The subcutaneously administered APOE mimetics were reported to significantly improve behavior, while decreasing the inflammatory cytokine IL-6, as well as decreasing neurofibrillary tangle-like and amyloid plaque-like structures. These improvements are associated with apoE mimetic-mediated increases in protein phosphatase 2A (PP2A) activity. [Decreased PP2A levels in AD may be involved in formation of neurofibrillary tangles (NFTs) which are aggregates of hyperphosphorylated tau; PP2A may also be involved in the production of Aβ peptides. The APOE mimetic are thus potential AD therapeutics.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.