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CANCER IMMUNOTHERAPY


CANCER IMMUNOTHERAPY

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

KNOWLEDGE-BASED APPROACHES FOR CANCER IMMUNOTHERAPY TARGETS

BY RICHARD K. HARRISON   

http://stateofinnovation.thomsonreuters.com/knowledge-based-approaches-for-cancer-immunotherapy-targets

The field of cancer immunotherapy is in its infancy but has already led to a major shift in the treatment of cancer – and this is only the beginning

Cancer is the second leading cause of death in the US, accounting for almost a quarter of US deaths.1 The American Cancer Society estimates the total worldwide economic impact of cancer at $900 billion annually.2 Until recently, treatments largely relied on nonspecific toxic compounds that showed limited success. But treatment paradigms are beginning to change and an old observation about tumors and the immune system may be responsible for a new wave of cancer treatments.

Using the immune system to regulate cancer progression traces its roots back to the 1890s when William B. Coley observed that bacterial infection often coincided with cancer regression. Coley developed the theory that post-surgical infections had helped patients to recover better from their cancer by provoking an immune response. He later reported the successfully creation of a filtered mixture of bacteria and bacterial lysates to treat tumors.3 The field progressed little over the following century until the comparatively recent explosion of research which has identified the mechanisms by which cancer cells evade detection by the immune system. Armed with this knowledge, researchers have identified several protein targets, most notably Programmed Cell Death-1 (PD-1)4 and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)5, and more importantly, antibodies that act on these targets resulting in the activation of the immune system towards the targeting of cancer cells.

http://stateofinnovation.thomsonreuters.com/sites/default/files/content/figures-charts/HOTSOI111611fig1.jpg

FIGURE 1: Cause of Death in the US, 2013

 

These findings have yielded unprecedented success in the treatment of certain cancers and ushered in the era of cancer immunotherapy.6 However, several cancers have proven refractory to PD-1 and CTLA-4 targeted therapies. For these diseases new classes of targets and new mechanisms must be identified. 7

 

http://stateofinnovation.thomsonreuters.com/sites/default/files/content/figures-charts/HOTSOI111611fig2.jpg

FIGURE 2: Components of the Immune System with targets for Cancer Immunotherapy

Identifying these new targets is arguably the most important step in the multimillion dollar drug discovery process. Fewer than 1 in 10 compounds that enter clinical trials becomes a medicine.8 Most fail because they are not effective against the disease they are designed to combat.9 Often these failures can be traced back to not selecting the right target to drug.10

To address this challenge Thomson Reuters analysts are applying knowledge based approaches and scouting biological pathways for potential new targets for immune based therapies for cancer. Our knowledge comes from a combination of retrospective analysis of ongoing development programs coupled with information extracted from the literature. We use this evidence to better understand the role of the immune system in fighting cancer.

http://stateofinnovation.thomsonreuters.com/sites/default/files/content/figures-charts/HOTSOI111611fig3.jpg

FIGURE 3: Targets for cancer immunotherapy

Better Targets For Existing Approaches

Scouting known targets for cancer immunotherapy and interrogating the regulators of these targets is one method to identify new potential targets. As an example we researched PD-1, the well-known checkpoint protein mentioned above. Analysis of the known transcriptional regulators of PD-1 highlighted that the majority of PD-1 expression is centered on activation of the JAK/STAT pathway and that targeting these proteins may represent a novel way to modulate the activity of PD-1. In addition, we uncovered interesting biomarkers for patient stratification or combination drug targets such as IFN-, NOTCH1, and the STATs.

 

http://stateofinnovation.thomsonreuters.com/sites/default/files/content/figures-charts/HOTSOI111611fig4.jpg

FIGURE 4: Signaling Pathways leading to the expression of PD-1

Novel Targets for New Approaches

For novel targets we performed analysis of publically available gene sets of cancer patients to identify differentially regulated genes. Interrogating the differentially expressed genes and superimposing these onto proprietary canonical pathway maps for immune response we are able to identify several targets that can serve as starting points for immunotherapy drug discovery, biomarkers for disease progression, and for stratifying patients for clinical trials.

The field of cancer immunotherapy is in its infancy but has already led to a shift in the treatment of cancer. Instead of treating the cancer, researchers are treating the immune system which in turn specifically targets only the cancer. And that is just the beginning. The knowledge gained from this research can be applied to diseases other than cancer, ushering in a new era of immunotherapy. Not a bad outcome even if it took over 100 years to come about.

For more detail on this topic, download the slide presentation given by author Richard K. Harrison, Thomson Reuters Chief Scientific Officer, at the Molecular Med Tri-Con 2016: “Knowledge Based Approaches to New Targets in Cancer Immunotherapy.”

To learn more about themes covered at the Molecular Med Tri-Con 2016, read the BioWorld special report.

References:
1. Globacan, International Agency for Research on Cancer; “Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. (2012).
2. American Cancer Society Cancer Facts and Figures. (2013).
3. Coley WB, The Treatment of Malignant Tumors By Repeated Inoculations of Erysipelas: With A Report of Ten Original Cases.
The American Journal of Medical Sciences 10, 487-511 (1893).
4. H. Nishimura, M. Nose, H. Hiai, N. Minato, T. Honjo, Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying
immunoreceptor. Immunity 11, 141-151 (1999).
5. K. M. Lee et al., Molecular basis of T cell inactivation by CTLA-4. Science 282, 2263-2266 (1998).
6. A. Swaika, W. A. Hammond, R. W. Joseph, Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol. Immunol. 67, 4-17 (2015).
7. A. C. Anderson, Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol. Res 2, 393-398 (2014).
8. J. Arrowsmith, A decade of change. Nat. Rev. Drug. Discov. 11, 17-18 (2012).
9. J. Arrowsmith, P. Miller, Trial watch: phase II and phase III attrition rates 2011-2012. Nat. Rev. Drug. Discov. 12, 569 (2013).
10. P. Morgan et al., Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival.
Drug Discov.Today 17, 419-424 (2012).
 
CLINICAL TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY

BY BETH KIERNAN   http://stateofinnovation.thomsonreuters.com/clinical-trends-and-challenges-in-immuno-oncology

Within immuno-oncology, checkpoint inhibitors and therapeutic cancer vaccines exhibit unique trends and challenges

Immunotherapy trials comprise more than one third of the current clinical oncology space. As innovators race to market, challenges inherent in immuno-oncology (I/O) are being met. Predictive and prognostic biomarkers have become notoriously difficult to pinpoint and regulatory bodies are struggling to maintain pace with the burgeoning field.

In taking a closer look at the 2,500 active I/O clinical trials in Cortellis Clinical Trials Intelligence, there are two classes experiencing interesting trends, each with their unique challenges. Therapeutic cancer vaccine trials have seen a shift in sponsors while steadily decreasing in number. Checkpoint inhibitors, meanwhile, have been rapidly gaining momentum.

Therapeutic Cancer Vaccines

Specialized biotech companies and research institutions have taken on the challenge of therapeutic cancer vaccine development. Following Dendreon’s success in 2010 with Provenge (sipuleucel-T), the only therapeutic cancer vaccine approved by the FDA thus far, drug developers are employing diverse strategies to effectively introduce cancer vaccines to immuno-compromised patients while mitigating adverse or unintended effects. Although the majority of therapeutic cancer vaccine studies are in the early stages, approximately 10 percent are those that have progressed to late-stage trials. These numbers indicate both an interest in the class as well as modest success with trial candidates.

FIGURE 1: Active, commercial immuno-oncology trials.   (SOURCE: Cortellis Clinical Trials)

Checkpoint Inhibitors

On the opposite end of the spectrum, checkpoint inhibitor trials are exhibiting a rapid-fire growth pattern and tremendous success. Since 2010, they have experienced a twenty-fold increase in the number of commercially relevant trials as compared to those started in 2015. Anti-CTLA-4 trials comprise a quarter of the current space, while target newcomers, PD-1 and PD-L1, make up the remainder, with PD-1 being studied in more than half of current trials.

PD-1 is a receptor on T-cells and binds ligands PD-L1 and PD-L2 to prevent T-cell activation. Upregulation of these proteins causes cancer cells to go unnoticed by the immune system. Inhibiting this checkpoint, however, lifts the veil, allowing the immune system to launch an attack. Both big pharma and biotech companies are active in the space and are taking on trials at almost double the rate of therapeutic vaccines.

BMS, following up on their success with Yervoy (CTLA-4) and Opdivo (PD-1), are at the top of the space, followed by Merck (Keytruda, PD-1) and Roche. Early and late phase trials are split down the middle indicating both interest in the space and successful progression to phase III trials. Until recently, melanoma has been the top indication in the space; however it has since been surpassed by lung cancer.

Advanced metastatic cancers, those where other treatments have failed, remain the top patient segments in checkpoint inhibitor trials. Challenges in this space lie in identifying predictive and prognostic biomarkers. Correlating response rate to the PD-L1 biomarker, which is currently seen in 39 percent of checkpoint inhibitor trials measuring biomarkers, is not always possible.

Conclusion

Immuno-oncology is a highly marketable and dynamic space currently led by checkpoint inhibitors. However, as niches become saturated, developers must look to identify novel approaches. Immunotherapy and cross-class combinations are proving to be successful, and the recent approval of Amgen’s oncolytic virus (T-vec) for inoperable melanoma is giving hope that there are opportunities beyond T-cells. Our immune system is a complex defense structure full of cells ready to take on the fight against cancer – they just need the right orders.

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One Response

  1. on April 12, 2016 at 2:20 PM | Reply sjwilliamspa

    Cortellis by Thompson Reuters is a very good system.



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