Off-the-shelf T cell therapies for multiple myeloma

August 9, 2017

Although a source of much hope among 'multiple myeloma' (MM) patients, adoptive T cell therapies are still held back by expensive, lengthy, individual-tailored approaches. However, an EU-funded project is aiming to shake things up with off-the shelf solutions of its own.

There are currently three main approaches for obtaining therapeutic T : the isolation, expansion and reinfusion of tumour-infiltrating lymphocytes (TILs); the ex vivo generation and expansion of tumour antigen-specific T cell lines; and the genetic engineering of autologous T cells with tumour antigen-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs). But whilst the feasibility and effectiveness of these approaches have all been proven in clinical settings, all these approaches have to be tailored to the patient before they can be applied.

With this in mind, the CARIPSCTCELLS (Generation of safe and efficient, off-the-shelf, chimeric antigen receptor (CAR)-engineered T cells for broad application) project has developed technology that will enable in vitro, unlimited, safe and broadly applicable T cells targeting MM. Dr Maria Themeli, coordinator of the project, discusses its results.

Why are T cell therapies so rarely used?

Current strategies for obtaining therapeutic T cells have limitations. Their use is restricted to specialised institutes and specific patient populations. The isolation and ex vivo manipulation of autologous cells require expensive specialised equipment, good manufacturing practice (GMP) facilities and trained personnel. In many cases, the autologous T cell isolation and expansion would be problematic or impossible, for instance in immunosuppressed patients after chemotherapy or immune-deficient patients presenting malignancies.

Moreover, the production of autologous therapeutic cancer-specific T cells requires processing times which can be critical for the patient's health. Sometimes the patient dies before receiving the therapy. This all makes the production of therapeutic T cells an expensive process, which is difficult to be broadly applied.

How did your project aim to solve these problems? How did such solutions come about?

We thought that the development of broadly applicable cellular therapeutics, which have been manufactured, functionally validated and banked in advance, and can be applied beyond histocompatible Human leukocyte antigen (HLA) barriers, would improve the consistency and availability while reducing the cost of adoptive T cell therapy. With this goal in mind, we explored the feasibility of a novel strategy for generating unlimited, 'off-the-shelf', safe, antigen-specific T lymphocytes with optimised features.

We propose the use of induced (iPSC) as a source of T lymphocytes. These cells can be cultured in the lab without limit and can be differentiated to T lymphocytes. In addition, they can be genetically manipulated easily, so that the final T cell product will possess specific desirable immunotherapeutic characteristics. For example, we can provide cancer antigen specificity through an artificial CAR and delete the expression of HLA molecules to make them histocompatible.

Why did you decide to focus specifically on MM?

The department of haematology at VUmc Amsterdam is one of the biggest European centres for MM patient care. What makes us so interested in this disease is that although there has been much progress in delaying the course of the disease, it still remains incurable. Therefore, we focus our research on finding novel, potentially curative therapies. To this end, we have developed and preclinically evaluated the use of CD38-targeting CAR-T cells for the treatment of MM.

How was the CRISPR/Cas9 system beneficial to your research?

The CRISPR/Cas9 technology has revolutionised the field of gene therapy over the last few years. With this technology, modifying the genome has become easier and safer, since it allows for highly specific gene editing. We use this system in order to genetically modify the cells in the iPSC stage and achieve specific optimised features when they differentiate into therapeutic T cells.

What would you say are the most important achievements of the project?

We have succeeded in generating genetically-modified iPSC, which give rise to broadly applicable 'off-the-shelf' T cells bearing an anti-myeloma CAR and eliciting anti-myeloma function without having histocompatibility restrictions.

What do you hope will be the long-term impact on MM treatment?

The development of 'off-the-shelf', applicable immunotherapeutic tools will lift immunotherapy from an individual basis and will allow the availability of controlled, validated and safe immunotherapeutics for a broad patient population.

MM is the second most common haematologic malignancy. Thus, a broadly applicable adoptive T cell immunotherapy would be of benefit for many patients. But most important, this project will lay the foundation for a new strategy for the broad application of iPSC-derived T cells, not only for targeting MM, but also for all CAR-based T cell therapies, since the results obtained from our studies could also be translated to other malignancies.

What are your follow-up plans, if any?

We aim to further pursue the goal of generating potent therapeutic T cells from iPSC. We will focus on further improving the therapeutic properties of the generated T cells from human iPSC by influencing and refining the in vitro differentiation mechanisms of phenotypic determination and by enhancing their persistence and effector function.

Explore further: What makes cancer gene therapy so groundbreaking?

More information: Project page: cordis.europa.eu/project/rcn/195614

Related Stories

What makes cancer gene therapy so groundbreaking?

July 19, 2017
On July 12, a Food and Drug Administration panel unanimously recommended approval for the first-ever gene therapy treatment for cancer. The treatment, known as CTL019, is a T-cell therapy developed by the pharmaceutical company ...

Special T cells that target solid tumors offer potential treatment for pediatric and adult cancers

September 14, 2016
Adoptive cell-therapies, in which a patient's own immune cells are used to recognize and target tumors, have shown breakthrough results for patients with certain B-cell malignancies, or cancers of the blood, but this therapy ...

CAR T cells more powerful when built with CRISPR, researchers find

February 22, 2017
Researchers from Memorial Sloan Kettering Cancer Center (MSK) have harnessed the power of CRISPR/Cas9 to create more-potent chimeric antigen receptor (CAR) T cells that enhance tumor rejection in mice. The unexpected findings, ...

N-acetyl cysteine improves efficacy of adoptive T cell immunotherapy for melanoma

October 14, 2016
A collaborative team of investigators at the Medical University of South Carolina (MUSC) and Loyola University have demonstrated for the first time that culturing T cells in N-acetyl cysteine (NAC) before they are infused ...

Induced pluripotent stem cells (iPSC) shown to form multiple types of functional lymphocytes in vivo

March 28, 2016
A new study demonstrates that iPSC have the potential to differentiate into multiple lineages of functional lymphocytes, including CD4+ T cells, B cells, and natural killer cells, without bias. The ability to generate truly ...

Recommended for you

Scientists develop blood test that spots tumor-derived DNA in people with early-stage cancers

August 16, 2017
In a bid to detect cancers early and in a noninvasive way, scientists at the Johns Hopkins Kimmel Cancer Center report they have developed a test that spots tiny amounts of cancer-specific DNA in blood and have used it to ...

Toxic formaldehyde is produced inside our own cells, scientists discover

August 16, 2017
New research has revealed that some of the toxin formaldehyde in our bodies does not come from our environment - it is a by-product of an essential reaction inside our own cells. This could provide new targets for developing ...

Cell cycle-blocking drugs can shrink tumors by enlisting immune system in attack on cancer

August 16, 2017
In the brief time that drugs known as CDK4/6 inhibitors have been approved for the treatment of metastatic breast cancer, doctors have made a startling observation: in certain patients, the drugs—designed to halt cancer ...

Popular immunotherapy target turns out to have a surprising buddy

August 16, 2017
The majority of current cancer immunotherapies focus on PD-L1. This well studied protein turns out to be controlled by a partner, CMTM6, a previously unexplored molecule that is now suddenly also a potential therapeutic target. ...

Researchers find 'switch' that turns on immune cells' tumor-killing ability

August 16, 2017
Molecular biologists led by Leonid Pobezinsky and his wife and research collaborator Elena Pobezinskaya at the University of Massachusetts Amherst have published results that for the first time show how a microRNA molecule ...

A metabolic treatment for pancreatic cancer?

August 15, 2017
Pancreatic cancer is now the third leading cause of cancer mortality. Its incidence is increasing in parallel with the population increase in obesity, and its five-year survival rate still hovers at just 8 to 9 percent. Research ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.