The American Society of Clinical Oncology (ASCO) held its 2012 Annual Meeting on June 1-5, 2012. Arguably the highlight of the meeting was the June 2, 2012 presentation by Bristol-Myers Squibb (BMS) on its Phase 1 immunotherapeutic, anti-PD-1 (BMS-936558). The results of this study were also published ahead of print on June 2, in the online version of the New England Journal of Medicine. Nature published a “News in Focus” article on the same subject by Nature staff writer Erika Check Hayden in its 6 June issue.

BMS acquired its anti-PD-1 MAb product BMS-936558 (MDX-1106) via its 2009 acquisition of Medarex. This is the same way in which BMS acquired its now-marketed immunotherapy, ipilimumab (Yervoy), which was approved by the FDA in March 2011. Both BMS-936558 and ipilimumab are monoclonal antibodies (MAbs). Ono Pharmaceuticals has been a partner in the development of anti-PD-1 MAb since its original collaboration with Medarex; Ono retains the right to exclusively develop and market the agent (which is also designated as ONO-4538) in Japan, Korea and Taiwan.

PD-1 (“programmed cell death-1”) is a receptor on the surface of activated T lymphocytes of the immune system. PD-1 is a member of the CD28/CTLA4 family of T cell regulators. Like CTLA4, the target of ipilimumab, PD-1 is a negative regulator of T-cell receptor signals. When a protein on the surface of some tumor cells, known as PD-1 ligand (PD-L1), binds to PD-1 on T cells that recognize antigens on these tumors cells, this results in the blockage of the ability of the T cells to carry out an anti-tumor immune response. Anti-PD-1 MAb binds to PD-1 on T cells, thus preventing PD-L1 on tumor cells from binding to the PD-1 and initiating an inhibitory signal. Anti-tumor T cells are then free to initiate immune responses against the tumor cells. This mechanism of action is completely analogous to that of ipilimumab, which binds to CTLA4 and thus prevents negative signaling from that molecule.

Phase 1 clinical study of Medarex/BMS’s anti-PD-1

The Phase 1 clinical study was carried out by a multi-institution team of investigators, led by Suzanne L. Topalian, M.D. (Johns Hopkins University School of Medicine, Baltimore, MD.) The researchers enrolled patients with advanced melanoma, non-small-cell lung cancer (NSCLC), prostate cancer, renal cell cancer (RCC), or colorectal cancer. Patients received anti-PD-1 at a dose between 0.1 and 10.0 milligrams per kilogram of body weight every two weeks. Tumor response was determined after each 8-week treatment cycle. Patients received up to 12 cycles of treatment until either unacceptable adverse events, disease progression or a complete response occurred. A total of 296 patients received treatment through February 24, 2012.

Among the 236 patients in whom tumor responses could be evaluated, objective responses were observed in patients with NSCLC, melanoma, or RCC. Cumulative response rates (among patients treated with all doses of anti-PD-1) were 18% among patients with NSCLC, 28% among patients with melanoma, and 27% among patients with RCC.  These responses were durable–20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. Anti–PD-1 produced objective responses in approximately one in four to one in five patients with NSCLC, melanoma, or RCC.

In addition to patients with objective responses, other patients treated with anti-PD-1 exhibited stable disease lasting 24 weeks or more–5 patients (7%) with NSCLC, 6 patients (6%) with melanoma, and 9 patients (27%) with RCC.

Significant drug-related adverse effects were seen in 11% of the patients, including three deaths due to pulmonary toxicity. In most cases, adverse effects were reversible, and the observed adverse-event profile does not appear to preclude the use of the drug. A maximum tolerated dose was not reached in this study.

The exciting finding of this study is that anti-PD-1 produced durable responses not only in melanoma and RCC (the two types of cancer that are deemed to be “immunogenic”), but also in NSCLC, a much more common cancer that kills more people per year than any other cancer. Moreover, response rates with anti-PD-1 were much higher that those achieved with the other recently approved immunotherapeutics. In the Phase 3 clinical trial of ipilimumab that led to its approval, this drug gave response rates of 11% in melanoma patients. The other recently approved immunotherapeutic, the prostate cancer-specific dendritic cell vaccine Sipuleucel-T (Dendreon’s Provenge, APC8015), gives very low response rates and no complete responses. According to Antoni Ribas (Jonsson Comp­rehensive Cancer Center, University of California, Los Angeles CA) as quoted Ms. Hayden’s Nature “News in Focus” review, if an immunotherapy “breaks the 10% ceiling” as did anti-PD-1, it becomes “even more important and clinically relevant”.

Despite the exciting efficacy results with anti-PD-1, and despite the fact that it was deemed that the adverse-event profile did not appear to preclude the use of the drug, researchers would still like to get away from the serious adverse effects (including three deaths) seen with anti-PD-1. As with other immunotherapeutics (e.g., ipilimumab), researchers hypothesize that anti-PD-1’s serious adverse effects were due to autoimmune responses.

Phase 1 clinical study of Medarex/BMS’ anti-PD-L1

A potential way of achieving similar efficacy to anti-PD-1 with an improved safety profile is provided by another Phase 1 immunotherapeutic,  anti-PD-L1. Anti-PD-L1 MAb drugs are being developed by Medarex/BMS, Roche/Genentech, and other companies. As mentioned earlier, PD-L1 is the binding partner of PD-1 that is expressed on some tumor cells. As quoted in the Nature “News in Focus” review, Ira Mellman (vice-president of research oncology at Genentech), believes that anti-PD-L1 might have fewer adverse effects than anti-PD-1. That is because anti-PD-L1 would target tumor cells while leaving T cells free to participate in immune networks that work to prevent autoimmune reactions.

The results of a Phase 1 clinical study of BMS/Medarex’ anti-PD-L1 (also known as MDX-1105) were also published ahead of print in the online version of the New England Journal of Medicine on June 2, 2012; this was a “companion study” to the Phase 1 study of anti-PD-1. This study was also carried out by a multi-institution team of investigators, led by Julie R. Brahmer, M.D. (Johns Hopkins University School of Medicine, Baltimore, MD.); Dr. Topalian, among other investigators on the anti-PD-1 trial, also participated in the study.

This Phase 1 trial was a dose escalation study that was carried out via a similar protocol to the anti-PD-1 trial discussed earlier. As of February 24, 2012, a total of 207 patients — 75 with NSCLC, 55 with melanoma, 18 with colorectal cancer, 17 with RCC, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody, for a median duration of 12 weeks. Among patients with an evaluable response, an objective response (i.e., a complete or partial response) was seen in 17% of patients with melanoma, 12% of patients with RCC, 10% of patients with NSCLC, and 6% of patients with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. Prolonged disease stabilization was seen in 12-41% of patients with advanced cancers, including NSCLC, melanoma, and RCC.

Significant drug-related adverse effects were seen in 9% of patients.

Although the two agents were not compared directly in a randomized trial, the frequency of objective responses for anti–PD-L1 MAb appears to be somewhat lower than that observed for anti–PD-1 MAb in initial Phase 1 trials; the frequency and severity of significant drug-related adverse events also appears to be lower. However, whether these differences will hold up in Phase 2 and 3 clinical trials remains to be determined. The clinically appropriate dose of anti–PD-L1 will also require further definition later studies. Nevertheless, the Phase 1 trial showed that anti-PD-L1 MAb induced durable tumor regression (objective response rate of 6-17%) and prolonged disease stabilization (rate of 12-41% at 24 weeks) in patients with select advanced cancers, including NSCLC, a tumor type that had been deemed to be “non-immunogenic”. This is essentially the same result that was observed for anti-PD-1MAb.

A predictive biomarker for treatment with anti-PD-1?

As with other modes of cancer therapy, it would be very useful to have mechanism-based predictive biomarkers to identify appropriate candidates for treatment with anti-PD-1 or anti-PD-L1 immunotherapy. The findings of the Phase 1 anti-PD-1 study suggest that PD-L1 expression in tumors is a candidate biomarker that warrants further evaluation for use in selecting patients for immunotherapy with anti–PD-1 MAb. The researchers found that 36% of patients with PD-L1–positive tumors achieved an objective response, while no patients with PD-L1–negative tumors achieved such a response. These results suggest that PD-L1 expression on the surface of tumor cells in pre-treatment tumor specimens may be associated with an objective response. However, further studies will be necessary to define the role of PD-L1 as a predictive biomarker of response to anti–PD-1 therapy. Similarly, it appears reasonable that tumor expression of PD-L1 may be a predictive biomarker of response to anti-PD-L1 therapy. However, this hypothesis must also be tested in further clinical studies.

Further studies of anti-PD-1 MAb

Two studies of BMS-936558/MDX-1106 anti–PD-1 MAb, both in advanced/metastatic clear-cell RCC, are now recruiting patients. One trial is a Phase 1 biomarker study involving immunologic and tumor marker correlates of efficacy (progression-free survival and tumor response). The other trial is a Phase 2 efficacy (progression-free survival and tumor response) study; this is a dose ranging study that is designed to determine if a dose response exists. Phase 3 studies of BMS-936558/MDX-1106 anti–PD-1 MAb for the treatment of non–small-cell lung cancer, melanoma, and renal-cell cancer are also being planned.

Conclusions

The exciting results of the studies with BMS’ anti-PD-1 and anti-PD-L1 have only been in Phase 1 studies. Thus caution is advisable in interpreting these results, pending the results of further clinical studies. Nevertheless, these results, together with the recent approval of ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy) and of Sipuleucel-T (Dendreon’s Provenge), indicate that cancer immunotherapy, a field that not so long ago was regarded as an impractical dream, is very much alive and well. In addition to clinical development and approval of immunotherapeutic agents, exciting basic and drug discovery research in this field is ongoing. This was recognized by the awarding of the 2011 Nobel Prize in Physiology or Medicine for research with profound implications for the development of cancer immunotherapies.

The Biopharmconsortium Blog has been covering new developments in cancer immunotherapy since the spring of 2011. Our earlier articles on this subject (with links) are listed in our December 31, 2011 article, entitled “Read the cancer immunotherapy review in the 22 December 2011 issue of Nature!”

Cancer immunotherapy represents one of several “scientifically premature” or “frontier science” areas discussed in this blog that are providing new opportunities for drug discovery and development–for young entrepreneurial biotech start-ups and for more established biotechnology and pharmaceutical companies. Corporate strategists would do well to explore such areas for potential new R&D programs for their companies.

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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.

RAS/BRAF/PI3K pathways. Source: Source BioScience

Two previous articles on this blog have included discussions of the “co-clinical mouse/human trial” strategy for improving mouse models of human cancer, and simultaneously improving human clinical trials of drugs for these cancers. Now comes an article on the use of a co-clinical trial strategy in personalized treatment of non-small cell lung cancer (NSCLC) in the 29 March 2012 issue of Nature. In the same issue of Nature is a News and Views article by Genentech’s Leisa Johnson Ph.D. that provides a minireview of the research article.

As we discussed in our April 15, 2010 article on this blog, the co-clinical trial strategy has been developed by Pier Paolo Pandolfi, MD, PhD (Director, Cancer and Genetics Program, Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center) and his colleagues.

As discussed in that article, these researchers constructed genetically engineered transgenic mouse strains that have genetic changes that mimic those found in human cancers. These mouse models spontaneous develop cancers that resemble the corresponding human cancers. In Dr. Pandolfi’s  ongoing co-clinical mouse/human trial project, researchers simultaneously treat a genetically engineered mouse model and patients with tumors that exhibit the same set of genetic changes with the same experimental targeted drugs. The goal of this two-year project is to determine to what extent the mouse models are predictive of patient response to therapeutic agents, and of tumor progression and survival. The studies may thus result in validated mouse models that are more predictive of drug efficacy than the currently standard xenograft models.

The human clinical trials being “shadowed” by simultaneous studies in mice included Phase 3 trials of several targeted therapies for lung and prostate cancer. Xenograft models in which tumor tissue from the patients had been transplanted into immunosuppressed mice were also being tested in parallel with the genetically engineered mouse models. This project represents the most rigorous test to date of how well genetically engineered mouse models of cancer can predict clinical outcomes.

Our October 28, 2011 blog article, which is mainly a review of a 29 September 2011 Nature article by Nature writer Heidi Ledford, Ph.D., focuses on ways to fix the clinical trial system. Our article includes a discussion of a co-clinical trial published in January 2011. This trial utilized two genetically-engineered PDGF (platelet-derived growth factor)-driven mouse models of the brain tumor glioblastoma multiforme (GBM), one of which had an intact PTEN gene and the other of which was PTEN deficient. In this trial, researchers tested the Akt inhibitor perifosine (Keryx Biopharmaceuticals, an alkylphospholipid) and the mTOR inhibitor CCI-779 (temsirolimus; Pfizer’s Torisel), both alone and in combination, in vitro and in vivo. The drugs and drug combinations were tested in cultured primary glioma cell cultures derived from the PTEN-null and PTEN-intact mouse PDGF-driven GBM models, and in the animal models themselves.

The studies showed that both in vitro and in vivo, the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null cells in animals was achieved by using both inhibitors in combination.  In vivo, the decreased Akt and mTOR signaling seen in mice treated with the combination therapy correlated with decreased tumor cell proliferation and increased cell death; these changes were independent of PTEN status. The co-clinical animal study also suggested new ways of screening GBM patients for inclusion in clinical trials of treatment with perifosine and/or CCI-779.

The new co-clinical trial reported in the March 2012 issue of Nature

The March 2012 Nature report describes research carried out by a large, multi-institution academic consortium, which included Dr. Pandolfi. It focuses on strategies for treatment of patients with non-small-cell lung cancer (NSCLC) with activating mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog). These mutations occur in 20–30% of NSCLC cases, and patients whose tumors carry KRAS driver mutations have a poor prognosis. Moreover, KRAS is a “hard” or “undruggable” target, and no researchers have thus been able to discover inhibitors of oncogenic KRAS.

Because of the intractability of oncogenic KRAS as a target, researchers have been attempting to develop combination therapies for mutant-KRAS tumors (including, for example, colorectal cancers as well as NSCLCs) that address downstream pathways controlled by KRAS. We discussed examples of these strategies in our book-length report Multitargeted Therapies: Promiscuous Drugs and Combination Therapies, published by Cambridge Healthtech Institute/Insight Pharma Reports in 2011. Strategies discussed in that report are based on the finding that KRAS controls signal transduction via two key pathways: the B-Raf-MEK-ERK pathway and the PI3K-Akt pathway. This is illustrated in the figure at the top of this article. As discussed in our 2011 report, researchers are attempting to develop treatments of mutant-KRAS tumors that involve combination therapies with an inhibitor of the mitogen-activated protein kinase (MEK) together with an inhibitor of phosphatidylinositol 3-kinase (PI3K). Researchers are also attempting to develop combination therapies of MEK inhibitors with standard cytotoxic chemotherapies, which if successful will avoid having to use combinations of two expensive targeted therapies.

In the co-clinical trial that is the focus of the 29 March 2012 Nature research report and News and Views commentary, researchers developed a genetically-engineered mouse model to study treatment of mutant-KRAS NSCLCs with either the antimitotic chemotherapy drug docetaxel alone, or docetaxel in combination with the MEK kinase inhibitor selumetinib (AZD6244, AstraZeneca). In the parallel human clinical trial, researchers are also studying treatment of patients with mutant-KRAS NSCLC with docetaxel alone or docetaxel plus selumetinib. (There is no treatment arm in the human clinical trial in which patients are treated with selumetinib alone, since selumetinib monotherapy of NSCLC patients had shown no efficacy in a previous Phase 2 study; this was confirmed in mouse model studies.)

In humans with mutant-KRAS NSCLC, many tumors with mutations in KRAS have concomitant genetic alterations in other genes that may affect response to therapy. Therefore, the co-clinical trial researchers wished to design mouse models with lung tumors with either Kras mutations alone or with mutations in both Kras and another gene that is often concomitantly mutated in mutant-KRAS NSCLCs in humans. The researchers therefore constructed mouse models with cancers bearing the activating Kras(G12D) mutation, either alone or together with an inactivating mutation in either p53 or Lkb1. The researchers achieved this via a conditional mutation system using nasal instillation of specifically genetically-engineered adenoviruses. As result, a small percentage of lung epithelial cells harbored these mutations. It is from these cells that the NSCLC-like tumors arose, analogous to the clonal origin of sporadic lung tumors in humans.

Of the two tumor suppressor genes that are frequently mutated in human mutant-KRAS NSCLCs and that were modeled by the co-clinical trial researchers, p53, often called the “guardian of the genome”, is familiar to most of you. The other gene, Lkb1 [liver kinase B1, also known as serine/threonine kinase 11 (STK11)], was discussed in an earlier article on the Biopharmconsortium Blog, entitled “The great metformin mystery–genomics, diabetes, and cancer.”

LKB1 (whether in regulation of gluconeogenesis in the liver or in its role as a tumor suppressor) acts by activation of AMPK (AMP-activated kinase, a sensor of intracellular energy status.) In lung cancer (as shown by the same group that performed the 2012 co-clinical trial), LKB1 acts to modulate lung cancer differentiation and metastasis.  Germline mutations in LKB1 are associated with the familial disease Peutz-Jegher syndrome, in which patients develop benign polyps in the gastrointestinal tract. Studying a mouse model of mutant-LKB1 Peutz-Jeger syndrome, Reuben J. Shaw (Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA, who was prominently mentioned in our “great metformin mystery” article) and his colleagues showed that the LKB1-AMPK pathway downregulates the mTOR pathway–specifically the rapamycin-sensitive mTOR complex 1 (mTORC1) and its downstream effector hypoxia-inducible factor-1α (HIF-1α). HIF-1α expression in turn upregulates the expression of its downstream effectors hexokinase II and glucose transporter 1 (GLUT1), which are involved in cellular utilization of glucose. LKB1-deficient polyps in this mouse model thus show increased expression of hexokinase II and GLUT1, resulting in dramatically increased glucose utilization.

In the new co-clinical trial, genetically-engineered mice that showed established lung tumors [as determined via magnetic resonance imaging (MRI)] were randomized to receive either docetaxel, selumetinib, or a combination of the two drugs. For tumors with only a Kras mutation, treatment with docetaxel alone resulted in a modest rate of response, with 30% of mice showing a partial response. Mice that bore mutant-Kras tumors that also had mutations in either p53 or Lkb1 had much lower rates of response to docetaxel monotherapy (5% and 0%, respectively), and more of these mice showed progressive disease on MRI or died of their disease. Of mice treated with the docetaxel/selumetinib combination, those with single-mutant Kras tumors showed a 92% overall response rate, and those with mutant Kras/p53 tumors showed a 61% overall response rate. However, mice with mutant Kras/Lkb1 cancers showed only a modest response to the docetaxel/selumetinib combination; 33% of mice achieved a partial response. The difference in response rate of mice with Kras/Lkb1 tumors to docetaxel/selumetinib compared to the other two genotypes was found to be statistically significant.

Using the genetically-engineered NSCLC mouse model in biomarker development

In human patients in clinical trials or in treatment for their cancers, performing repeated biopsies to monitor treatment is difficult. The co-clinical trial researchers therefore wished to develop less invasive means of monitoring both co-clinical and clinical trials of docetaxel/selumetinib treatment of NSCLC. They therefore tested the use of positron emission tomography (PET) with 18F-fluoro-2-deoxyglucose (FDG-PET) as an indicator of early response to therapy that could be used in the clinic.  Prior to its radioactive decay (109.8 minute half -life), 18F-FDG is a nonmetabolizable glucose analogue that moves into cells that is preferentially taken up by high-glucose utilizing cells. The researchers found that both Kras/p53 and Kras/Lkb1 tumors showed higher FDG uptake in vivo in the mouse model than did single-mutant Kras tumors. As expected from the earlier study, GLUT1 expression was elevated in Kras/Lkb1 mutant tumors. In human patients, pre-treatment, mutant KRAS/LKB1 tumors also showed a higher FDG uptake that did KRAS tumors negative for LKB1.

Treatment of the mice with docetaxel alone gave no significant changes in FDG uptake in Kras, Kras/p53, or Kras/Lkb1 tumors in vivo. However, within 24 hours of the first dosing of docetaxel/selumetinib, FDG uptake was markedly inhibited in Kras and Kras/p53 tumors. In contrast, treatment of mice with Kras/Lkb1 mutant tumors gave no appreciable decrease in FDG uptake in these tumors. These results show that early changes in tumor metabolism, as assessed by FDG-PET, predict antitumor efficacy of docetaxel/selumetinib treatment.

The FDG-PET study in this mouse model supports the use of this imaging method as a biomarker to monitor the course of treatment in humans.

Cellular signaling in mutant Kras, Kras/p53, and Kras/Lkb1 tumors

The researchers assessed activation of relevant intracellular pathways in tumors in treated and untreated mice with mutant Kras, Kras/p53, and Kras/Lkb1 lung cancers. They performed these studies using two different methods–immunostaining of cancer nodules for phosphorylated ERK, and immunoblotting of tumor lysates. In untreated mice, Kras/Lkb1 tumors show less activation of ERK than do Kras and Kras/p53 tumors, with Kras/p53 tumors showing the greatest amount of activation of the MEK-ERK pathway. Docetaxel had no discernible effect on signaling via the MEK-ERK pathway. Selumetinib alone resulted in decreased ERK activation in Kras and Kras/p53 tumors, but there was still residual activity. The docetaxel/selumetinib combination, however, was more effective in eliminating ERK activation. Pharmacokinetic studies indicated that selumetinib levels were higher in both serum and tumors of mice treated with docetaxel/selumetinib that in those treated with selumetinib alone; this might account for the more potent suppression of MEK-ERK signaling by the combination therapy as compared to selumetinib monotherapy. The researchers studied MEK-ERK activation (as determined by phospho-ERK staining) in  a set of 57 human NSCLC tumors with known RAS, p53 and LKB1 mutation status. As with the tumors in the mouse model, of seven patients whose tumors harbored the KRAS activating mutation, the three patients with concurrent p53 mutations showed higher levels of ERK activation.

The decreased activation of ERK in Kras/Lkb1 tumors suggested that these tumors utilize other pathways to drive their proliferation. On the basis of their prior studies of signal transduction in mutant-Lkb1 lung tumors, the researchers focused on AKT and SRC. Immunoblotting studies showed that Kras/Lkb1 mutant tumors had elevated activation of both AKT and SRC. As one can see from the figure at the top of this article, AKT is a downstream effector of PI3K; since the PI3K/AKT pathway regulates expression of GLUT1 and hexokinase, increased activation of the PI3K/AKT pathway is consistent with the increased uptake of FDG of mutant Kras/Lkb1 tumors. In the figure, SRC (which is not shown) represents one of the major “other effectors” controlled by RAS. These results indicate that concomitant mutation of Lkb1 in mutant-Kras NSCLCs may shift the signaling pathways that drive tumor proliferation from MEK-ERK to PI3K/AKT and/or SRC. This shift would result in primarily resistance of Kras/Lkb1 tumors to treatment with docetaxel/selumetinib.

Long-term benefits of treatment of mice with mutant-Kras and Kras/p53 tumors with docetaxel/selumetinib as opposed to docetaxel monotherapy

The researchers studied long-term treatment of mice with mutant-Kras and Kras/p53 tumors with docetaxel monotherapy versus docetaxel/selumetinib. In mice with mutant-Kras tumors, treatment with docetaxel monotherapy gave stable disease for several weeks, while docetaxel/selumetinib treatment resulted in tumor regression and slower regrowth of tumors. The addition of selumetinib to docetaxel significantly prolonged progression-free survival in these mice. In mice with Kras/p53 tumors, treatment with docetaxel alone resulted in progressive disease, but docetaxel/selumetinib treatment resulted in initial disease regression followed by progression, resulting in prolonged progression-free survival. These results indicate that treatment with combination therapy as opposed to docetaxel alone results in improved progression-free survival, but not cure, in mice with Kras– and Kras/p53-mutant tumors.

The researchers also investigated mechanisms of acquired tumor resistance in mice with mutant-Kras and Kras/p53 tumors, which had been treated long-term with docetaxel/selumetinib. In moribund animals that had received this treatment, all tumor nodules examined showed a recurrence of ERK phosphorylation. This suggested that acquired resistance could be at least in part due to reactivation of MEK–ERK signaling despite ongoing treatment with selumetinib. Evaluation of resistant tumor nodules suggested that more than one mechanism for pathway reactivation was occurring; study of these mechanisms is ongoing.

Conclusions of the new co-clinical study

The results of this co-clinical study predict that docetaxel/selumetinib combination therapy will be more effective than docetaxel monotherapy in several sub-classes of mutant-KRAS NSCLC. This prediction is consistent with the early results of a Phase 2 clinical trial of these two drug combinations in second-line treatment of patients with KRAS-mutant NSCLC.

However, the co-clinical trial also predicts that concurrent mutation of LKB1 in mutant-KRAS  tumors will result in primary resistance to docetaxel/selumetinib combination therapy, perhaps via activation of parallel signaling pathways such as AKT and SRC. Since LKB1 status is not being prospectively assessed in the ongoing human clinical trial, the presence of patients with cancers having concurrent LKB1 mutations may diminish the differences between treatment arms based solely on KRAS status. The results of the co-clinical trial suggests that researchers perform retrospective analysis of p53 and LKB1 status in samples from the concurrent human clinical trial. Future clinical trials should then be designed that involve prospective analysis to ensure sufficient enrollment of patients with all three genotypes to enable sufficiently powered sub-group analyses.

Although the results of the co-clinical trial indicate that patients with mutant KRAS/LBK1 tumors be excluded from trials of docetaxel/selumetinib treatment, the research group that has been conducting the co-clinical trial has also been conducting studies that may lead to treatment strategies for KRAS/LBK1 tumors.

The co-clinical trial also allowed researchers to design and validate biomarker strategies, specifically the potential use of the less-invasive FDG-PET to predict efficacy and to monitor treatment. The co-clinical animal-model study also enabled the discovery of mechanisms of both primary and acquired resistance that might benefit future clinical trials and discovery/development of drugs. (The studies on acquired resistance are in a early stage and are ongoing). Any mechanisms of acquired resistance discovered in co-clinical studies should be confirmed in human clinical trials by examining biopsy samples from patients who relapse on therapy. The ability to assess mechanisms of resistance in preclinical or co-clinical animal studies may enable researchers to design rational drug combination strategies that can be implemented in future clinical studies.

The results of the new co-clinical trial strengthens the contention that co-clinical trials in genetically-engineered mice can provide data that can predict the outcome of parallel human clinical trials. Co-clinical trials can also be used to generate new hypotheses for use in analyzing concurrent human trials, and for design of future clinical studies. Moreover, co-clinical trials can result in the validation of improved animal models for human cancers, which can be used in research and preclinical testing of oncology agents, and in validation of biomarkers for clinical studies in oncology. Given the inadequacy of “standard” xenograft models, which is a major factor in the high attrition rate of pipeline oncology drugs, the availability of validated genetically-engineered animal models may be expected to enable improved oncology drug development.

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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.

Salinomycin

On November 3, 2011, Cambridge MA biotech firm Verastem announced that it was filing a prospectus for an initial public offering (IPO). At that time, the company was 15 months old.

Verastem is led by Christoph Westphal, MD, PhD, a founder and the former CEO of Sirtris and a veteran entrepreneur and venture capitalist. The IPO has been underwritten by UBS, Leerink Swann, Lazard Capital Markets, Oppenheimer & Co., and Rodman & Renshaw.

On January 27, 2012, Fierce Biotech reported that Verastem had announced the previous night that its IPO raised $55 million from the sale of 5.5 million shares at $10 apiece. This price fell exactly in the middle of its expected $9 to $11 price range, and the company had even increased the offering by a million shares over what had originally been planned.

On the same day, Verastem’s stock opened at $11 a share on the NASDAQ, up from its initial public offering price of $10.

Verastem not only has Christoph Westphal as its Chairman and CEO, but is also based on science from eminent MIT researchers Robert Weinberg, Ph.D. and Eric Lander, Ph.D., and has several other well-respected academic researchers (including Nobelist Phillip Sharp, Ph.D.) plus biotech industry drug discoverers Julian Adams, Ph.D. (MIllennium’s Velcade) and Roger Tung, Ph.D. (Vertex’ Lexiva and Agenerase) on its Scientific Advisory Board. The company has had considerable fundraising success prior to its IPO, including raising $32 million in venture capital  in July 2011.

However, Verastem has not one lone drug in human clinical trials, its most advanced compounds are in the preclinical stage, and the company does not plan to file an IND until 2013! Thus Verastem has successfully gone public, in an era in which even most private biotech companies with drugs in late-stage clinical trials are finding it very difficult to do so, despite its lack of any clinical-stage drugs.

As noted in the Fierce Biotech article, Dr. Westphal as well as other venture capital funders of Verastem agreed to buy up to $16.3 million of the IPO. This in part explains the success of the IPO. As also noted by Fierce Biotech, with over 19 million common shares outstanding, the offering valued Verastem at $192 million.

We discussed Verastem in our August 2, 2011 Biopharmonsortium Blog article entitled “Development of personalized therapies for deadly women’s cancers”. Verastem focuses on discovery and development of drugs to target cancer stem cells. Its technology is based on a strategy for screening for compounds that specifically target cancer stem cells, developed by Drs. Weinberg, Lander, Piyush Gupta (MIT and Broad Institute) and their colleagues.

Cancer stem cells are best known in acute myeloid leukemia (AML), but their existence in other cancers (especially solid tumors) is controversial, as discussed in our article. Whether cancer stem cells are involved in the pathobiology of solid tumors (or a particular type of solid tumor) or not, the biology of the putative cancer stem cell phenotype can be important in certain subtypes of cancer. Cancer stem cells are characterized by the epithelial-mesenchymal transition (EMT). In the Cell paper, the researchers screened for compounds that specifically targeted breast cancer cells that had been experimentally induced into an EMT, and which as a result exhibited an increased resistance to standard chemotherapy drugs.   They identified the compound salinomycin (now being marketed as a generic veterinary antibiotic) as a drug that specifically targeted these cells, as well as putative cancer stem cells from patients.

As we discussed in our article, triple-negative (TN) breast cancer cannot be treated with standard receptor-targeting breast cancer therapeutics (e.g., tamoxifen, aromatase inhibitors, trastuzumab) but must be treated with cytotoxic chemotherapy. It is generally more aggressive than other types of breast cancer, and even treatment with aggressive chemotherapy typically results in early relapse and metastasis. However, TN breast cancer includes two experimentally defined subtypes that have gene expression signatures related to the EMT. One or both of these subtypes might therefore be expected to be sensitive to compounds that specifically target putative breast cancer stem cells. This may be true whether the cancer stem cell hypothesis applies to TN breast cancer or not. Verastem is focusing on TN breast cancer as its first therapeutic target.

Verastem’s VS-507, a proprietary formulation of salinomycin, is being developed to treat TN breast cancer. The company is also screening for additional compounds, including New Chemical Entities (NCE) that can achieve stronger intellectual property protection than a salinomycin formulation. Verastem had not chosen a lead compound as of the middle of 2011. The company is now reported to be doing preclinical studies on three of its compounds, and also plans to create diagnostic tests to identify patients that could benefit from its treatments. (As we discussed in our article, biomarker-based tests will be critical in making such therapies work.)

As one can discern from our blog article, we are intrigued by Verastem’s approach to cancer treatment, and especially its approach to TN breast cancer. The science behind Verastem’s drug discovery strategy, developed by 2011 ASCO award-winning oncogene and cancer stem-cell pioneer Bob Weinberg, is very compelling. We would love to see Verastem’s therapeutic strategy succeed.

However, as virtually all pharmaceutical and biotechnology R&D researchers well know, it is difficult to translate even the most compelling science developed by the most brilliant researchers into the clinic. Even therapeutic strategies with an excellent scientific rationale that have achieved proof of principle in the best animal models can result in clinical failure, especially with the first compound tested in proof-of-concept studies in human patients. The cancer stem cell hypothesis remains controversial. Moreover, diseases such as TN breast cancer are complicated, they may have mechanisms of resistance to a new experiential therapy that no one knows about, and our understanding of disease biology is limited.

Thus at least until Verastem’s therapies achieve proof of concept in human studies, purchase of Verastem stock is risky indeed. Moreover, there are other risks involved other than technical and clinical risk–especially competition for developing cancer stem cell-based therapies by other biotech/pharma companies. Venture capitalists (and certain knowledgeable individual investors and funds) are in the business of taking on high-risk investments for the sake of potential large rewards, but ordinary retail investors in the public markets are not. Therefore, it seems too early for Verastem to go public, even if it has founders and investors with enough clout to make an IPO successful.

Expert analysts in the IPO field, as stated in the Fierce Biotech article, are puzzled by the rationale for Verastem going public at this time. The financial news and services website “TheStreet.com” agrees. Our own sense of puzzlement is symbolized by the interobang (‽) in the title of this article.

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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.

Happy New Year! http://bit.ly/tKUKIR

We commend for your New Year’s reading the review article entitled “Cancer immunotherapy comes of age” in the 22 December 2011 issue of Nature. It was written by Drs. Ira Mellman (Genentech),  George Coukos (University of Pennsylvania School of Medicine), and Glenn Dranoff (Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Center/Brigham and Women’s Hospital and Harvard Medical School, Boston, MA).

As you may recall, Genentech’s Dr. Mellman was mentioned in our November 25, 2011 blog article on Dr. Ralph Steinman. Dr. Mellman was a former member of Dr. Steinman’s lab, and he was one of the researchers who helped plan the strategy for the immunotherapy-based treatment of Dr. Steinman’s own pancreatic cancer.

The review by Dr. Mellman and his colleagues is truly comprehensive. It covers research and events in drug development in cancer immunotherapy that we also discussed in the following 2011 blog articles:

• March 30, 2011: FDA approves ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy) for treatment of metastatic melanoma.

• April 27, 2011: Adoptive immunotherapy for metastatic melanoma? 

• November 25, 2011: Ralph Steinman, dendritic cell vaccines, and clinical trials.

• December 26, 2011: The 2011 Nobel Prize in Physiology or Medicine–Innate and Adaptive Immunity.

The Nature review ties all these subjects and events together, and gives additional in-depth information on each of them. For example, in discussing adoptive immunotherapy for cancer with tumor infiltrating lymphocytes (TILs), the review presents new studies on the use of T-cell engineering and bispecific antibodies. Such methods may enable researchers and clinicians to get beyond the need for resectable tumors harboring reactive T cells, or even allow them to stimulate TILs in situ, thus avoiding the need to isolate and culture autologous T cells altogether.

Both the new Nature review and the discussions on our blog show that 2011 was a big year for cancer immunotherapy. The past year was proceeded by the 2010 approval of the first ever cancer vaccine, sipuleucel-T (Dendreon’s Provenge) for prostate cancer. 2011 saw the approval of ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy), and the awarding of a Nobel Prize for discoveries with profound implications for the development of cancer immunotherapies.

The importance for cancer immunotherapy of the discoveries represented by this Nobel Prize was vividly illustrated by the survival of Ralph Steinman an almost incredible four-and-a-half years after his being diagnosed with pancreatic cancer, while receiving a series of immunotherapy treatments along with conventional chemotherapy. (Although there is no way to know whether any of the treatments was responsible for Dr. Steinman’s unexpectedly long survival, participating researchers agree that this one-patient experimental treatment moved the cancer immunotherapy field forward.)

The Nature review concludes that despite the long history of cancer immunotherapy, these are early days for research and clinical practice in the field. (This is typical for a premature technology! Nevertheless, the review concludes, cancer immunotherapy has come of age.

The review goes on to suggest that cancer immuntherapies might be used in combination with the new targeted therapies, such as vemurafenib (Plexxikon/Roche’s Zelboraf; PLX4032) and crizotinib (Pfizer’s Xalkori), which were approved in 2011. These targeted agents can give “significant and sometimes spectacular responses in several indications.” However, even the most dramatic responses are usually followed by drug resistance and relapse. If targeted therapies can be given with the appropriate immunotherapies, it might be possible to achieve long-term, durable responses.

This is the last article on the Biopharmconsortium Blog for 2011. We at Haberman Associates wish you all a very Happy New Year, and look forward to interacting with you in 2012.
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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.

Blood cells

Our November 25, 2011 article on this blog focused on Ralph Steinman, one of the three winners of The Nobel Prize in Physiology or Medicine for 2011. That article focused on dendritic cell-based vaccines for cancer, and the application of this area of science and technology to treating Dr. Steinman’s own pancreatic cancer. Dr. Steinman died on September 30, 2011 after a four-and-a-half year battle with his disease, and was awarded the Nobel Prize three days later. He is the only person to ever have been awarded a Nobel Prize posthumously.

Now comes a Nobel Prize Essay, in the December 9, 2011 issue of Cell, entitled “Bridging Innate and Adaptive Immunity”, written by William E. Paul (Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH”). It is immediately followed by an obituary for Ralph Steinman, written by Antonio Lanzavecchia and Federica Sallusto (Institute for Research in Biomedicine, Bellinzona, Switzerland).

The Nobel Prize in Physiology or Medicine for 2011 was divided, one half awarded jointly to Drs. Bruce A. Beutler (Scripps Research Institute, LA Jolla, CA and University of Texas Southwestern Medical Center, Dallas, TX) and Jules A. Hoffmann [National Center of Scientific Research (CNRS), Strasbourg, France] “for their discoveries concerning the activation of innate immunity” and the other half to Dr. Ralph M. Steinman (Rockefeller University, New York, NY) “for his discovery of the dendritic cell and its role in adaptive immunity”. So the focus of this year’s Nobel Prize in Physiology or Medicine is on the two arms of the immune response–innate and adaptive immunity, and the relationship between the two.

Innate and adaptive immunity in the early to mid-20th century

Dr. Paul’s essay is a historical exposition of how researchers came to understand the basis of the innate and the adaptive immune responses, and how they work together as a coherent system. Adaptive immunity focuses on the ability of a vertebrate organism to “learn” to respond to a specific new antigen, and to “recall” and respond to an antigen that it had been exposed to in the past. Innate immunity focuses on the ability of nearly all multicellular life forms, including plants, to respond rapidly to protect themselves against pathogens, using the inflammatory system.

The essay begins with the first ever Nobel Prize given for a discovery in immunology, in 1908. This was shared by two pioneers in the field–Paul Ehrlich and Ilya (or Élie) Metchnikoff. Ehrlich pioneered the study of what is now called adaptive immunity. His work in immunology focused on the ability of humans and animals to develop specific antibodies to toxins such as tetanus toxin and diphtheria toxin. Metchnikoff pioneered the study of what is now called innate immunity. His work resulted in the discovery of phagocytosis, the process by which certain white blood cells can ingest and destroy harmful microbes.

As outlined in Dr. Paul’s article, most of the attention of immunologists between the awarding of the 1908 Nobel Prize and the modern era was on adaptive immunity, focused on the clonal selection theory of immunity and on discoveries in the the cellular (e.g., T cells) and humoral (e.g., antibodies) arms of adaptive immunity. A key practical application of the study of adaptive immunity–from Ehrlich’s day to the present–has been the development of vaccines.

Adjuvants and Charles Janeway’s pattern recognition hypothesis

However, mid-20th century immunology had a “dirty little secret”. Immunization with a pure antigen produces either a very weak immune response, or immune tolerance. In order to obtain a strong immune response, it is necessary to co-inject an adjuvant along with the antigen. The creation of adjuvants–which is involved not only in experimental immunology, but in such practical applications as vaccines–has been something of a black art. Adjuvants used in vaccines include  oil emulsions (which are thought to serve as depots for an antigen) and aluminum hydroxide (which is thought to act as an irritant). The most famous adjuvant in experimental immunology is complete Freund’s adjuvant, a strong adjuvant that consists of killed Mycobacteria tuberculosis bacteria in a water-in-oil emulsion. (Complete Freund’s adjuvant is too toxic for use in humans.)

In 1989, the late Dr. Charles Janeway (Yale University, New Haven, CT) proposed a hypothesis to explain the need for adjuvants; this hypothesis was very fruitful in stimulating further research on the immune response. Dr. Janeway hypothesized that the immune system required both an antigen/receptor interaction (as in classic adaptive immunity) and a recognition of pathogen-associated molecular patterns (PAMPs). PAMPs would be recognized by “pattern-recognition receptors” (PRRs), which would be broadly expressed by immune and inflammatory cells. Recognition of PAMPs by cells carrying PRRs would result in an innate immune response, which would be interpreted by cells of the adaptive immune system, the lymphocytes, as “permission” to mount an adaptive response when they recognized a specific antigen. In vaccination, the function of an adjuvant would be to provide the needed PAMPs.

Drs. Hoffman and Beutler and innate immunity

Beginning in 1996, Jules Hoffmann and his colleagues elucidated the innate immune response pathway in the fruit fly Drosophila, which enables the fly to produce the antifungal peptide drosomycin, and thus to become resistant to fungal infection. This pathway is initiated by the cell surface receptor Toll, and is homologous to the interleukin 1 (IL-1)/NF-κB signaling pathway, which is a key pathway in vertebrate immune and inflammatory responses.

Dr. Janeway and his colleagues then followed up on this study, in order to identify the corresponding microbial sensors in humans. They first scanned a molecular biology database, and identified a transcript that encoded a human homologue of Drosophila Toll, which they named a “Toll-like receptor” (TLR). Since Dr. Janeway and his colleagues did not know the ligand for their TLR, they constructed a chimeric molecule in which the extracellular domain of CD4 was linked to the cytoplasmic domain of the TLR. They expressed this chimera in a human monocyte cell line. When the chimera was crosslinked with an anti-CD4 antibody, NF-κB was activated, resulting in the production of the proinflammatory cytokines IL-1, IL-6, and IL-8. This showed that humans had at least one Toll homolog (Dr. Janeway’s TLR turned out to be TLR4) and that it controlled a signaling pathway similar to those controlled by Drosophila Toll or human IL-1. The ligands for human TLRs remained unknown, as did whether TLRs were the microbial sensors/PRRs postulated by Dr. Janeway had postulated.

It was Bruce Beutler who first determined the nature of TLR recognition specificity. In the 1990s, he worked to identify the genetic defect that rendered some mice unresponsive to lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, which acts as an endotoxin in humans and other mammals. He used two closely related mouse strains, one of which was responsive to LPS (the “wild type” strain), and the other that was unresponsive (the “mutant” strain). Upon stimulation with LPS, macrophages from the wild type mouse produced tumor necrosis factor alpha (TNFα), while macrophages from mutant mice did not. Dr. Beutler used positional cloning to determine the gene that was mutant in the LPS unresponsive mice. In 1998, he and his colleagues reported that that gene was Tlr4, which codes for the very same TLR identified by Dr. Janeway and his colleagues a year earlier. Dr. Beutler’s study indicated that LPS was a direct or indirect ligand for TLR4. It also showed that one type of molecule that would fulfill the criteria for a “PAMP”, namely LPS, working via TLR4 as a “PRR”, could activate the NF-κB-IL-1 pathway.

Since the initial identification of TLR4 by Dr. Beutler and his colleagues, other researchers have identified numerous other TLRs, which are activated by a variety of bacterial and viral molecules. These include such types of molecules as single- and double-stranded RNAs, CpG oligodeoxynucleotides, bacterial flagellin, lipopeptides, and zymosan, all of which fit with Dr. Janeway’s PAMP hypothesis. Different TLRs occupy different subcelluar locations–some are on the cell surface, others in intracellular vesicles. In addition to TLRs, other types of molecules may also act as PRRs.

Dr. Steinman, dendritic cells, and the unification of innate and adaptive immunity

Now we come to the work of Ralph Steinman and his colleagues on the role of dendritic cells in adaptive immune responses, and their relationship to innate immunity.

Antibodies (whether free antibodies or antibodies on the surface of B cells) can recognize molecules on the surface of pathogens. T cell receptors, however, recognize small antigenic peptides carried by major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). This recognition, together with the activity of other signaling molecules on APCs, results in the activation of the T cell.

The requirement for an APC in T-cell activation was first recognized in the late 1960s and early 1970s. At that time, immunologists generally believed that macrophages and perhaps B cells were the major APCs. In 1973, Ralph Steinman and Zanvil Cohn identified mouse dendritic cells, which are rare cells in the spleen and lymph nodes that have a stellate morphology. In 1978, Dr. Steinman and his colleagues published evidence that dendritic cells had potent immunostimulatory activity, and were over 100 times as effective in immunostimulation as macrophages and B or T cells.

Researchers were initially skeptical about Dr. Steinman’s studies, largely based on the widely held view that the far more numerous macrophages were the major APCs. However, a series of studies by Dr. Steinman and his colleagues showed that dendritic cells are the key APCs for nearly all aspects of T cell activation, and that the potency of dendritic cells as APCs far exceeds that of macrophages and B cells.  Indeed, modern techniques that led to the deletion of dendritic cells result in a profound inability to mount adaptive immune responses.

Dendritic cells are found in perhaps every type of tissue, where they exist in an immature state. For example, the population of immature dendritic cells in the skin are known as Langerhans cells–these cells are illustrated in the figure at the top of our November 25, 2011 article. Immature dendritic cells in tissues act as sentinels of microbial infection, and function to capture antigens (e.g., antigens from pathogenic microbes, or from cells infected by viruses or bacteria). They also express TLRs.

When tissue dendritic cells are stimulated via their TLRs (e.g., by TLR4 binding to bacterial LPS), the dendritic cells change to a mature phenotype, which is specialized in antigen presentation. These mature dendritic cells migrate from the tissue into the draining lymph node. The stimulated dendritic cells in the lymphoid system upregulate class II MHC molecules and other cell surface molecules involved in antigen presentation, and they also produce cytokines involved in T cell activation. The dendritic cells thus activate T cells, and the antigens presented on their surface, as well as the pattern of cytokines they produce, determine the specificity and the type of activated T cells that will result from their actions.

Thus, the work of Dr. Steinman and his colleagues serves to integrate studies of innate and adaptive immunity, and to elucidate how these two branches of the immune system work together to enable humans and other vertebrates to mount immune responses against pathogens and other insults such as tumors.

Despite the major advances in the relationship between innate and adaptive immunity that have been made in recent years, their are still many unknowns. For example, there are minority types of T cells such as natural killer T (NKT) cells and gamma-delta (γδ) T cells, which are conventionally thought to be involved in bridging innate and adaptive immunity. However, their functions are not well understood. Moreover, there are also numerous subsets of dendritic cells, and the functions of these subsets is also not well understood. These cell types, and other unknowns in the relationship between innate and adaptive immunity might, for example, be involved in the pathogenesis of steroid-resistant asthma, the most serious type of asthma.

Implications for drug discovery and development

Our previous article on Ralph Steinman and dendritic cells emphasized the development of dendritic cell vaccines, especially those for cancer. However the broad area of the relationship between innate and adaptive immunity has been and is expected to be a major factor in discovery and development of many types of drugs, vaccines, and immunotherapies.

• Numerous cytokine-based therapies (e.g., interferons, interleukins, and TNF-related therapeutics) have already been developed and marketed. Dr. Beutler himself was the co-discoverer of TNFα in 1985,  and now there are several types of TNF inhibitors on the market.

• In the vaccine area, Dr. Steniman’s work may allow researchers to design more effective adjuvants, a key need in the design of novel anti-viral and anti-cancer vaccines.

• Several companies are developing TLR modulators as drugs or vaccine adjuvants. These include TLR agonists and antagonists. For example, Pfizer is developing the oligonucleotide TLR9 agonist vaccine adjuvant CpG7909 (in Phase 3 trials with GlaxoSmithKline’s MAGE-A3 melanoma vaccine), and another oligonucleotide TLR9 agonist product agatolimod, in combination with trastuzumab (Genentech/Roche’s Herceptin) in treatment of breast cancer (Phase 2). [Pfizer’s TLR agonists were originally developed by Coley Pharmaceuticals (Cambridge, MA), which Pfizer acquired in 2008.] TLR antagonists in development include Eisai’s eritoran tetrasodium, a TLR4 antagonist in Phase 3 trials for the treatment of sepsis and septic shock.

• Research on the role of various immune cell populations that are thought to link innate and adaptive immunity (e.g. Th17 cells, NKT cells, and γδ T cells) in steroid-resistant asthma may lead to the design of new medicines to treat this serious condition.

There are likely to be numerous other drug discovery and development applications of research on the relationship between innate and adaptive immunity that will emerge as work in this very complex area continues.
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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.