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Immunotherapy in Myeloma Horizons Infosheet Clinical Trials and Novel Drugs Immunotherapy in myeloma Horizons Infosheet Clinical trials and novel drugs This Horizons Infosheet provides information on immunotherapy, a type of treatment being investigated in myeloma. The Horizons Infosheet series What is immunotherapy? provides information relating Immunotherapy is a type of cancer to novel drugs and treatment treatment which helps the immune strategies that are currently being system to recognise and kill cancer investigated for the treatment of cells. Many myeloma treatments are myeloma. The series also aims to immunotherapies. highlight the considerable amount of research currently taking place in What is the immune system? the field of myeloma. The immune system is made up of The drugs and novel strategies specialised cells, tissues and organs described in the Horizons Infosheets which work together in a process may not be licensed and/or known as an immune response. An approved for use in myeloma. You immune response protects the body may, however, be able to access from foreign organisms (such as them as part of a clinical trial. bacteria or viruses) that enter the body. Infoline: 0800 980 3332 1 The immune system also identifies of mechanisms, allowing them and kills faulty or abnormal cells in to multiply and grow in the body. the body. Immunotherapy stimulates the immune system to work harder or White blood cells, produced in the smarter to kill myeloma cells. bone marrow, are an important part of the immune system. Different The complexity of the immune types of white blood cell, such as system means that there are plasma cells and T cells, perform many ways in which it can be specific immune functions. harnessed, and many of the different substances produced as part of the Plasma cells immune response can now be made Plasma cells make antibodies (also in the laboratory. known as immunoglobulins) and release them into the bloodstream. Immunotherapy currently in use Antibodies flag foreign or potentially There are a number of myeloma harmful organisms for removal by treatments already in use that work other cells of the immune system. partly through immunotherapy. Myeloma cells are abnormal plasma Allogeneic (donor) stem cell cells which produce a large amount transplantation works by harnessing of a single type of antibody, known the immune system of a healthy as paraprotein, which has no useful donor to attack a patient’s function. myeloma cells. However, the risk of T cells serious side effects is greater with T cells are immune cells that allogeneic stem cell transplantation circulate around the body scanning than autologous (self) stem cell for abnormal or infected cells. T cells transplantation, meaning that it is can either directly kill and remove only appropriate for a small number abnormal or infected cells, or they of myeloma patients. can stimulate healthy plasma cells to make antibodies and flag the cell For more information see the for removal. Allogeneic stem cell transplantation in myeloma Infosheet from How does immunotherapy Myeloma UK in myeloma work? Myeloma cells are able to evade the immune system through a variety 2 myeloma.org.uk The ‘immunomodulatory drugs’ Cells in the body (including (IMiDs) thalidomide, lenalidomide abnormal ones like myeloma cells) (Revlimid®) and pomalidomide all have antigens on their surface as (Imnovid®), are widely used in well. Antigens on abnormal cells can myeloma. They work in several also be targeted by antibodies. different ways including directly Each antibody recognises only killing myeloma cells. They also one antigen, and so millions of stimulate the immune system, which antibodies are produced by the body increases their effect. to defend against a range of foreign Daratumumab (Darzalex®) is a drug organisms or abnormal cells. licensed in the UK to treat myeloma. Monoclonal antibody drugs It is a type of immunotherapy exploit the ability of antibodies to called a monoclonal antibody (see recognise specific antigens. They following section for more about this are engineered in the laboratory type of drug). to recognise antigens specific to myeloma cells so that the immune Immunotherapies system can be directed to recognise in development and kill them. ‘Monoclonal’ means The main types of immunotherapies all one type. This means that each now being investigated for the monoclonal antibody drug is made treatment of myeloma are: up of identical copies of one type of antibody that recognise one specific • Monoclonal antibody drugs antigen, in this case a protein that is expressed by myeloma cells • CAR-T cell treatments (Figure 1). Oncolytic viruses • monoclonal monoclonal antibody drug antibody drug Monoclonal antibody drugs Foreign organisms such as viruses and bacteria have proteins on their cell surface (known as antigens) that are specific to that organism. myeloma myeloma Healthy plasma cells produce cell cell antibodies which recognise and proteins proteins on the cell on the cell surface surface attach to antigens, flagging the monoclonal monoclonal antibody locked antibody locked organism for destruction by other onto the cell- onto the cell- immune cells, such as T cells. surface protein surface protein Figure 1. Mechanism of action of monoclonal antibody drugs. Infoline: 0800 980 3332 3 Monoclonal antibodies are an Antibody drug conjugates established treatment in myeloma Drugs are also being developed and in many other cancers, with which combine a monoclonal some showing huge promise antibody with a chemotherapy in the treatment of myeloma. drug (known as an antibody- Daratumumab (Darzalex®), was the first drug in this group to be drug conjugate) to guide the approved for myeloma in the UK. It chemotherapy directly to the is available as a monotherapy (given myeloma cells. One of these, ® on its own) for patients who have belantamab mafodotin (Blenrep ), had three previous drug treatments, was recently licensed for use in and as a combination treatment for Europe. It contains the powerful patients at first relapse. chemotherapy drug mafodotin joined to an antibody. Mafodotin is In late 2020, a second monoclonal too toxic to be given on its own, but antibody, called isatuximab in the conjugate it only becomes (Sarclisa®), was approved for active once the antibody had guided patients in England and Wales. It it to a myeloma cell. is available in combination with pomalidomide and dexamethasone for patients who have had three For more information see the previous treatments. Belantamab mafodotin Horizons Infosheet from Myeloma UK For more information see the Daratumumab (Darzalex®) Treatment T cell engagers Guide and the Isatuximab (Sarclisa®) Antibodies called T-cell engagers Horizons Infosheet from Myeloma UK recognise two antigens, one on the myeloma cells and one on T Another monoclonal antibody drug currently being investigated cells. This brings the T cells and for the treatment of myeloma is myeloma cells into close contact, elotuzumab. and targets the T cell activity to the myeloma cells (see Figure 2). T cell For more information see the engagers are at an earlier stage Elotuzumab (Empliciti®) Horizons of development than some other Infosheet from Myeloma UK types of immunotherapy. One T cell engager currently in early clinical trials is called AMG 701. 4 myeloma.org.uk on the surface of myeloma cells. The MYELOMA T cells can then target and kill the CELL patient’s myeloma cells. proteins on the cell CAR-T cells are used in a process surface proteins on the cell called adoptive T cell transfer. T surface cells are collected from a patient’s BiTE forming a blood and genetically modified in a link between the myeloma cell laboratory, forming CAR-T cells. The and the T cell by locking onto the cells are then multiplied and infused T CELL cell surface proteins. back into the patient (Figure 3). Following the infusion, the CAR-T Figure 2. Mechanism of action of BiTEs cells continue to multiply within the patient’s body and target and kill CAR-T cell treatments myeloma cells. CAR (chimeric antigen receptor) T Results of trials with CAR-T cell cell treatments are a personalised treatments have so far have been treatment. This means the promising with good remission treatment is tailored to an individual rates in relapsed and/or refractory patient. In this case, a patient’s own patients. However, the CAR-T T cells are taken and modified so cells do become exhausted (stop that they recognise a specific target 1. T cells are removed 1. T cells are removed from patient from patient T cell T cell DNA DNA 4. T cells target and 4. T cells target and modified kill myeloma cells modified kill myeloma cells gene gene 2. genetic 2. genetic modification 3. patient receives modification 3. patient receives of T cells modified T cells of T cells modified T cells Figure 3. Adoptive T cell transfer process Infoline: 0800 980 3332 5 working) eventually. Because CAR-T Oncolytic viruses cell treatments are tailor-made for Oncolytic viruses infect and kill an individual patient, they are very cancer cells, while having only a costly, and there is a delay of a limited effect on normal cells. number of weeks while the CAR-T When an oncolytic virus infects cells are produced. CAR-T cell a myeloma cell, it continues to treatments currently in development multiply within the myeloma cell include idecabtagene vicleucel until the cell bursts. This causes (also called ide-cel or bb2121), and the myeloma cell to die and release JNJ-4528. The European Medicines the virus into the surrounding area Agency and the UK drug approval (Figure 4). The virus then goes on to body (NICE) are currently looking at infect other myeloma cells, causing ide-cel for relapsed and refractory them to also die. myeloma patients. At the same time, the virus causes For more information see the the immune system to mount an CAR-T cell treatments Infosheet from immune response against the the Myeloma UK myeloma cell.
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