MICA: Optimising combination strategies for chimeric antigen receptor therapy in multiple myeloma

Myeloma is a cancer of the bone marrow which affects over 5000 new patients a year in the UK, is largely incurable, and the vast majority of patients will eventually die of their disease.

We now understand the immune system has an important part to play in myeloma. The immune system is a complex army of cells that the body uses to protect itself. T-cells are part of this army and are used to kill and stop infections. T-cells don't usually attack cancers for two main reasons. Firstly, T-cells do not recognize myeloma cells as being abnormal (since they come from our own cells and are not infected) and hence do not target them. Secondly, cancer cells have found ways to protect themselves- often by surrounding themselves with proteins and cell types which block the immune system. These so called immune-suppressive mechanisms are well described in myeloma.

Immunotherapy are new treatments which redirect the immune system to fight cancer. Recently a method has been developed to obtain T-cells from cancer patients, modify them to kill cancer and then return them to patients as a drip. This strategy overcomes the lack of recognition of cancer by T-cells and these engineered T-cells live and grow in the patient and attack cancer cells as if they were infected cells (called chimeric antigen receptors or CAR T-cells). This has been successful in leukemia and lymphoma and although myeloma patients do respond to CAR T-cells, not as well.

The reason why CAR T-cell therapy doesn't work very well in myeloma is due to the second problem. The immune-suppressive mechanisms that stop normal T-cells from recognising and killing cancer cells likely affect modified T-cells too- reducing their killing potential. There are two possible strategies to combat this: first, several chemical and protein drugs can disrupt the ways cancer cells develop to protect themselves from the immune system. CAR T-cells can be combined with such drugs. Alternatively, CAR T-cells can be engineered in additional ways to make them resistant to suppression.

However, we do not yet have enough knowledge of the immune suppressive mechanisms in myeloma, or of how they can affect the CAR T-cells. So we do not know which are the key suppressive pathways to overcome. There are also too many available drugs and chemicals so that it is not feasible to test all possible combinations and there are currently no established ways of testing this on the benchtop or in mice.

The aim of my project is to gain knowledge of the mechanisms by which myeloma evades CAR T-cells. I will then use this knowledge to find the best way to combine CAR T-cells with strategies to overcome the suppressive immune system to make them as effective as possible in treating myeloma.

During my PhD, I developed a CAR T-cell strategy for myeloma which is now being tested in the first CAR T-cell trial for myeloma patients in the UK. I will start by studying the immune cells from patients on the clinical study who are being treated with CAR T-cells, so I can learn how the CAR T-cells behave after entering the patients. I will be able to compare the immune system in patients who respond, to those who do not. This will help us to understand which are the immune cells and immune suppressive mechanisms that are important if patients are to respond to CAR T-cell therapy.

I will also study cells in the laboratory, combining different types of immune cells, to test the behaviour of CAR T-cells in killing myeloma cells. I will develop and use a mouse model of myeloma, that has an intact immune system, as this model will allow me to study in more detail how the myeloma immune system interacts with CAR T-cells than has been possible before.

The results of these studies will provide important information to help design and then test treatments that could be used with CAR T-cells to make them more efficient at eradicating myeloma cells, and even potentially cure this cancer.

Myeloma(MM) remains incurable and following the success of chimeric antigen receptors(CARs) in B cell malignancies, CAR T-cells are being tested in MM. However, despite clinical responses, the suppressive immune microenvironment(IME) is well described in MM and likely to explain the high CAR T-cell doses needed in patient studies. The co-administration of immunomodulatory drugs or appropriate T-cell engineering may counter suppressive pathways. However, the suppressive IME in MM following CAR therapy is not clearly understood.

This fellowship will focus on the suppressive IME in MM, to provide the evidence base for effective combination strategies to optimise CAR T-cell therapy and improve patient outcome. Specific aims:

1)Characterise the IME effects on CAR T-cells
a)The APRIL-CAR, developed during my PhD, is the only MM CAR in clinical trials in the UK. Bone marrow (BM) samples from the APRIL-CAR clinical trial will be analysed by flow and CyTOF and findings clinically correlated with outcome. Solid BM biopsy samples will be studied by chip-cytometry- a novel method allowing multi-parametric analysis of tissues. b)The effects of putative immune suppressive cell types on CAR function will be studied by in vitro culture systems using autologous suppressor cells, and pathways identified evaluated using blocking antibodies or CRISPR editing. c)Developing the first CAR/MM model in immunocompetent mice will allow study of the interaction between CAR T-cells and the IME in vivo. Data by flow, immunohistochemistry and RNAseq of bone marrow, will validate this model against findings in patient samples to assess its clinical applicability

2) Design of rational combination strategies
With insight gained, strategies involving a)immunomodulatory agents or b)T-cell engineering will be tested in vitro/in vivo using systems outlined above with the aim of selecting combinations which significantly enhance disease control to take forward for clinical testing.

Rationalising use of immunotherapy has proven difficult. Healthcare Providers in particular are struggling to resolve the high cost of these expensive therapies (as single agents or in combination) with the equitable provision of effective treatments. I strongly believe that combination strategies are required to maximize the potential of CAR T-cell therapy in myeloma and this will make a difference to patient outcome. However, the choice of combinations has to be rooted in deep insight into the function of these therapeutics and their interaction with host immunity. Without this, the field will be unable to achieve the best possible patient outcomes that justifies public expense.

We are truly realising the dawn of immunotherapy in myeloma. It thus becomes necessary to train individuals to lead this field. This fellowship will equip me with the scientific and clinical skillset to actively contribute to this field and I will hope to contribute to a growing pool of UK clinical researchers adept at developing innovative immune therapies that can be rapidly developed for application in patients.