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    Amgen’s Growing Immunotherapy Arsenal Amgen’s Growing Immunotherapy Arsenal

    When it comes to enlisting the cancer-fighting potential of the body’s immune defenses, Amgen believes versatility is a virtue.

    Our immune cells are specialized to detect and vanquish foreign invaders, which may explain why they often lose the battle against internal enemies. Cancerous tumor cells grow and spread in stealth mode, and our immune system sometimes fails to recognize the danger.

    Since different cancers use different tricks to thwart the immune response, Amgen is developing a diverse set of countermeasures. The goal is to actually cure patients by developing customized therapies and hitting tumors from multiple angles simultaneously.

    BiTE® Antibodies

    Amgen’s largest investment in cancer immunotherapy research aims to expand the number of tumors that can be treated with BiTE® antibodies (bispecific T cell engagers). Amgen has been developing and enhancing the BiTE platform since 2012. In the past five years, Amgen

    • Gained the first regulatory approval for a BiTE antibody.
    • Advanced three more investigational BiTEs into clinical trials.
    • Built a discovery and early development pipeline of more than a dozen BiTE programs targeting a broad array of cancers.

    BiTE technology has been clinically validated in liquid tumors, and different BiTE molecules are now being tested in patients with non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, acute myelogenous leukemia, and multiple myeloma. Amgen is also working to extend the platform into solid tumors through BiTEs that aim to treat glioblastoma and cancers of the lung, pancreas, and ovaries.

    A Versatile Platform

    The breadth of investigational BiTEs underscores the flexibility of the platform, which is rooted in this modality’s structure and function. BiTEs are engineered antibody-based constructs that work by forming a bridge between a cancer cell and a T cell. The resulting proximity enables T cells to recognize cancer cells and destroy them (see illustration). The T cell-binding arm remains the same on all BiTE antibodies, but the tumor-targeting arm can be changed to engage different antigens found on different tumor types. Unlike many cancer drugs which require a target that cancer cells need to survive, BiTEs only require targets that are selectively expressed on the surface of cancer cells.

    Selectivity is a crucial factor in BiTE design, since T cells are the immune system’s most potent weapon. Amgen is continually refining its ability to identify targets that are highly selective for cancer cells, with little or no expression on most healthy cells. For example, AMG 420 aims to treat multiple myeloma by targeting B-cell maturation antigen (BCMA). This protein is strongly expressed on the plasma cells that become malignant in myeloma, but it is not widely expressed on other cell types.

    Engineering new forms of BiTEs

    Amgen’s protein engineers are also designing BiTE antibodies with enhanced features. First-generation BiTEs have a short duration of activity in the body, so they must be administered by continuous infusion, either in the hospital or with a wearable pump. Amgen is developing half-life extended BiTEs that could potentially be infused on a once-a-week basis.

    One arm of the BiTE® antibody constructs binds to CD3, an antigen found on the surface of T cells. The other arm is engineered to bind to a tumor-associated antigen (TAA). When both arms are bound to their targets, the T cells form a pore in the wall of the cancer cells, and toxic molecules flow through the pore, leading to the death of the cancer cell.

    Oncolytic Immunotherapy Viruses

    It was more than 100 years ago that doctors first observed that a viral infection can drive cancer into remission. The mutations in cancer cells can weaken a tumor’s ability to fight viruses, leaving it more susceptible to infection than normal cells. Oncolytic immunotherapy viruses aim to exploit this weakness in two ways.

    Killing tumor cells directly

    Oncolytic viruses are engineered to replicate in tumor cells but not in healthy cells (see illustration). Viral replication can cause the treated tumor cells to lyse, or burst open, releasing more viruses into the tumor environment, where they can infect and kill other tumor cells.

    Stimulating a broader immune response

    The virus can be designed to produce human proteins that summon immune cells to the tumor, where they encounter antigens released by destroyed tumor cells. The goal is to program the immune system to recognize tumor-associated antigens and to attack cells elsewhere in the body that carry these same antigens.

    Amgen has been developing this technology platform since 2012 and is the first company to gain regulatory approval for an oncolytic immunotherapy virus. This therapeutic approach is being tested in a variety of cancers, both alone and in combination with other immunotherapies. Amgen is sponsoring studies in patients with melanoma, head and neck cancer, liver cancer, and other non-CNS tumors.

    Ongoing Research

    In addition to its clinical research program, Amgen’s discovery scientists are exploring ways to enhance this novel technology. The therapy is currently administered by direct injection into tumors to ensure the virus reaches and infects tumor cells. This requirement makes it more challenging to treat tumors that are deep inside the body. It may be possible to design a virus that could be administered systemically by intravenous infusion or injection. Amgen is also exploring other immune-stimulating proteins that could be added to the virus to boost the immune response to tumor metastases.

    An oncolytic immunotherapy virus can be modified by inserting, deleting, or inactivating various genes. The goals are to create a virus that will 1) replicate selectively in tumor cells, causing them to burst and expose tumor antigens to the immune system, and 2) summon immune cells to the site of the tumor.

    CAR T Cells

    In 2015, Amgen and Kite Pharma launched a cancer immunotherapy collaboration to develop and commercialize chimetic antigen receptor (CAR) T cells, a novel, evolving technology with significant treatment potential. CARs are genetically engineered protein constructs that can be incorporated into a patient’s own T cells to redirect them to recognize and attack tumors.

    The collaboration combines Kite’s expertise in engineering and manufacturing CAR Ts with Amgen’s experience in antibody engineering and cancer target identification. That skill set has been sharpened by Amgen’s extensive work with BiTE® antibodies (bispecific T cell engagers), which also function by spurring T cells to distinguish and strike cancer cells.

    BiTEs and CAR Ts share several important attributes:

    • Both are potent and versatile platform technologies with the potential to treat many different types of cancers.
    • Both rely on targeting regions borrowed from antibodies to differentiate cancer cells from healthy cells.
    • Both require careful evaluation of tumor biology to ensure that a chosen target is tumor specific in order to mitigate potential safety risks.

    CARs and BiTEs also have important distinctions. Once manufactured, BiTEs can be used in any patient with the specific form of cancer they are approved to treat. CAR T cells are a single-component system based on a patient’s own T cells and manufactured for individual patients.

    In contrast to BiTEs, CARs can also have a much longer duration of activity. This extended activity can provide a large benefit for patients, but it also underscores the need to design CARs that target tumors selectively with minimal impact on healthy tissue. Through years of experience in advancing BiTEs into clinical studies, Amgen has developed rigorous methods for identifying tumor-specific targets as well as strategies for mitigating potential risks. That expertise is being applied to the Amgen-Kite collaboration, which now includes several programs at the discovery stage.

    It is possible that BiTEs and CAR T cells will have varying levels of efficacy and safety in patients with different types of cancer, or even the same cancer. To expand the therapeutic options available to patients, Amgen is exploring a broad range of BiTEs and CARs, including some directed at the same target.

    The CAR T cells engineered by Kite Pharma include an antibody-derived target binding domain, a costimulatory domain, and an essential activating domain. The first domain aims to make the T cell highly selective for cancer cells. The latter domains ensure that when CAR T cells engage tumor targets they become activated, proliferate, and kill tumor cells. (Illustration adapted from Kite Pharma.)

    Listeria-based Immunotherapy

    Listeria monocytogenes is a species of bacteria with attributes that give it great potential as an immunotherapy vector. Amgen and Advaxis are working to realize this potential through a novel technology platform called ADXS-NEO. This investigational therapy is a personalized Listeria-based vaccine. It’s designed to meet the needs of individual cancer patients by producing an immune response to multiple, specific mutations found only in their tumor cells.

    Targeting a key cell in the immune system

    The collaboration aims to leverage Amgen’s deep and broad experience in immuno-oncology with two novel platforms pioneered by Advaxis.

    • A technology called MINE (My Immunotherapy Neo-Epitopes) uses in-depth DNA sequencing to identify a wide range of tumor neoantigens—mutated protein fragments—that are found in a patient’s tumor cells but not healthy cells.
    • The Advaxis Lm Technology employs a weakened strain of Listeria as a vehicle to smuggle the genes for apatient’s tumor-specific mutations into antigen-presenting cells (APCs).

    Listeria make an ideal vector for a vaccine because these bacteria have evolved to target and live inside APCs. Once inside the cell, the engineered bacteria secrete tumor-associated proteins, which are processed by the APCs and presented to T cells (see illustration). This stimulates the T cells to recognize cancer cells with these same mutations and attack them.

    A large payload

    ADXS-NEO can be engineered to carry a payload of numerous tumor antigens—up to 100 or more if needed. This feature of the vaccine is designed to address the genetic diversity found in tumors. “The cancer cells in a patient’s body don’t all express the same number or kinds of antigens,” said Roger Sidhu, a global product general manager at Amgen who chairs the Amgen-Advaxis Joint Steering Committee. “This new approach could generate antitumor T cells that target a broad spectrum of the cells present in a tumor. We see that as an exciting potential advantage.”

    Into the clinic

    An Investigational New Drug application for ADXS-NEO was accepted by the FDA in March 2017, paving the way for the start of phase 1 studies. “We look forward to our continued work with Advaxis to explore the ground-breaking potential of ADXS-NEO in the clinic and across multiple tumor types,” said David Reese, Amgen’s senior vice president for Translational Sciences.

    The Listeria used in ADXS-NEO include DNA plasmids that produce the same tumor neo-antigens found in a patient’s tumor. Inside the body, the Listeria are taken up by antigen presenting cells, or APCs (1), where the bacteria secrete tumor-associated antigens into the liquid interior of the APC (2), which are then processed and presented to T cells (3). The goal is to help T cells to recognize a wide range of tumor-associated antigens and attack cancer cells with the same antigens (4).

    Orthogonal Combinations

    As the number and type of cancer immunotherapies expand, the potential for using different immune-boosting agents in combinations expands as well. Amgen’s strategy places an emphasis on orthogonal combinations—pairing treatments with distinct mechanisms of action to attack cancer from multiple angles.

    “With new treatment platforms like BiTEs and virus-based oncolytic immunotherapy, a lot of the long-term value to patients will come from combining these agents with other therapies,” said Sean Harper, Amgen’s executive vice president for R&D.

    Heating up “cold” tumors

    For example, there is early evidence that cancers treated with bispecific T cell engagers may respond by producing more immune-suppressing checkpoint proteins, like PD-1, to blunt the assault by T cells that BiTEs produce. Research also shows that immune-activating checkpoint inhibitors are more effective in “hot” tumors, which are infiltrated and inflamed by T cells, than in cold tumors which are not.

    This suggests that BiTEs and checkpoint inhibitors have the potential, in some cancers, to work synergistically, with BiTEs inflaming cold tumors by attracting T cells to the tumor environment, and checkpoint agents thwarting the tumor cells’ efforts to inactivate these T cells. Amgen and Merck are launching a study in 2017 to assess the effects of a BiTE and a PD-1 inhibitor in patients with diffuse large B cell lymphoma.

    Amgen expects this to be the first of many studies that pair BiTEs with other mechanisms. “Our BiTE platform is central to our immuno-oncology strategy, and we believe that BiTE constructs will be the foundation for many curative combinations in many different settings,” said Angela Coxon, an executive director in Amgen’s Oncology Research group.

    Oncolytic virus and checkpoint inhibitors

    Treatment with an oncolytic immunotherapy virus can also increase the level of inflammation in tumors and so potentially enhance the response rate to checkpoint inhibitors. Amgen and Merck have studied this combination in patients with melanoma. The results were encouraging, and the two companies are now mounting a phase 3 study in more than 600 melanoma patients to determine if adding an oncolytic immunotherapy virus to PD-1 inhibition improves survival in these patients.1

    1. Accessed May 15, 2017.