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Immuno-oncology is based on the concept of directing the attention of the body’s own immune system to tumors and harnessing it to respond to themStage Image

Immuno-oncology is based on the concept of directing the attention of the body’s own immune system to tumors and harnessing it to respond to them

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Avelumab

Immuno-oncology: Forcing cancer to come out of hiding

2015/8/19

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Immuno-oncology focuses on harnessing a patient’s immune system to fight cancer. The body’s immune system naturally detects and destroys cancer cells; however, cancer cells use various mechanisms to avoid detection and escape destruction.

  • Andrew Schiermeier, General Manager of the Immuno-Oncology Alliance
  • Andrew Schiermeier, General Manager of the Immuno-Oncology Alliance
    © Merck KGaA, Darmstadt, Germany

    Rather than targeting cancer cells with cytotoxic agents or biologicals, as is the case in classic oncology, with immunotherapies, the immune system is activated and directed to the tumor cells. Essential to this mechanism is the need to remove the checkpoints that allow tumors to avoid detection.  Molecules that target these checkpoints or inhibit them will help bring the tumor out of hiding and allow the immune system to attack the tumor.  Avelumab* is also thought to work according to this principle.

    The principle of checkpoint inhibition: Inhibiting the tumor’s defense mechanism and enabling immune system activation


    The editors of scientific journals are not known to shout for joy. But that is exactly what the editors of the prestigious publication Science did when they declared cancer immunotherapy, and thus checkpoint inhibition, to be the Breakthrough of the Year 2013. Immunotherapies are an age-old dream in medicine. They aim to expose cancer and to enable the immune system to fight the tumor. The discovery of checkpoint proteins (or simply “checkpoints”) has provided scientists with a tool that may put this target goal within reach. Experts think that immuno-oncology will soon become the fourth pillar of oncology, besides surgery, radiation therapy, and chemotherapy. Merck KGaA, Darmstadt, Germany and Pfizer have formed an alliance that focuses on the checkpoint inhibitor, avelumab, whose effectiveness and safety are being investigated in an extensive clinical study program targeting many different types of tumors.

    “The ability to harness the immune system to attack tumor cells has been shown to have broad application across many types of cancers.“

    Andrew Schiermeier
    General Manager of the Alliance and head of Global Oncology

    Rethinking oncology


     Checkpoints work like molecular brakes, curtailing immune reactions that have already begun in order to prevent “collateral damage” to the surrounding tissue. This is necessary because immune reactions need a starting point and an endpoint. Two of these checkpoint proteins are PD-1 and PD-L1. While PD-1 is located on immune cells (e.g. T-cells), PD-L1 is located on many different cells throughout the human body.
    When these two proteins meet, the white blood cells step on their molecular brakes, in order to stop the immune reaction. Cancer cells exploit this principle to camouflage themselves. They evade the immune system’s attack by accumulating PD-L1 proteins on their surface. These proteins are recognized by the PD-1 on the T-cells, thus blocking the body’s immune reaction against cancer. As a result, the tumor cells remain hidden. However, using antibodies which target the PD-L1 protein may allow the immune system to re-engage and attack the tumor.

    Two partners — one goal


    In addition to the re-engagement of T-cells as described above, avelumab is an antibody that was designed to have the structure of a natural human IgG1 antibody. In this way, it retains its normal function of activating the immune system’s killer cells, which may contribute to its effectiveness. Merck KGaA, Darmstadt, Germany, discovered this antibody nearly ten years ago and has investigated its potential in numerous studies. The company has formed an alliance with Pfizer, the number two company on the global pharmaceuticals market, for the co-development of avelumab. If successful, the companies will also co-commercialize avelumab. Pfizer made an upfront payment of US$ 850 million to Merck KGaA, Darmstadt, Germany, and may be eligible to receive further regulatory and commercial milestone payments of up to approximately US$ 2 billion under the terms of the agreement. 

    This alliance and the associated record amounts of funding underscore the importance that the pharmaceutical industry accords to checkpoint inhibition in oncology. “The ability to harness the immune system to attack tumor cells has been shown to have broad application across many types of cancers,” says Andrew Schiermeier, General Manager of the Alliance and head of Global Oncology.
  • Merck KGaA, Darmstadt, Germany, is pressing ahead with research on the anti-PD-L1 monoclonal antibodyEnlarge
  • Merck KGaA, Darmstadt, Germany, is pressing ahead with research on the anti-PD-L1 monoclonal antibody
    © Merck KGaA, Darmstadt, Germany

    This is also made clear by the design of the Phase I study of avelumab (clinicaltrials.gov identifier: NCT01772004), in which more than 1,000 patients suffering from a wide variety of solid tumors have participated to date. Some of the patients suffered from skin or ovarian cancer, while others had gastric cancer, non-small cell lung cancer, mesothelioma or other tumors. “Because patients with different types of tumors are being treated within the same Phase I trial simultaneously, we can more quickly collect data to determine the types of cancer for which the development of avelumab could be the most promising,” adds Schiermeier. “The Phase I study design serves as a scouting process that lets us identify `signals of efficacy` and estimate the likelihood of success more quickly.”  Avelumab is also under investigation in a Phase III clinical trial in non-small cell lung cancer (clinicaltrials.gov identifier: NCT02395172), a Phase II clinical trial in Merkel cell carcinoma (clinicaltrials.gov identifier: NCT02155647) and a Phase I clinical trial in solid tumors in Japanese subjects (clinicaltrials.gov identifier: NCT01943461).

    A broad clinical program


    Together, the alliance will collaborate on up to 20 clinical programs, including up to six pivotal trials expected to commence this year. In addition to pursuing avelumab as a monotherapy, the alliance is committed to investigating effective combinations for a variety of cancer therapies. Combination therapies are thought to potentially be more effective than monotherapies. With all of the excitement about immunotherapies, however, it is important to recognize that immuno-oncology is still in its infancy, and the alliance is still only beginning to understand the full potential of avelumab. If all goes according to plan and clinical results meet target endpoints, the first launch for avelumab is expected as early as 2017.

    2015/8/19

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    *Avelumab = proposed International Non-proprietary Name (INN), formerly referred to as anti-PD-L1 mAb (MSB0010718C). Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee it will be approved in the sought-after indications.

     
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