What does the approval of Kymriah mean for MPN patients?

This week the FDA approved a novel and exciting curative therapy for Acute Lymphoblastic Leukemia. The drug company Novartis’  Kymriah, also known as tisagenlecleucel, is what is known as Chimeric Antigen Receptor Therapy, or CAR-T, in which a patient’s own cells are extracted, re-engineered as cancer-fighting mini-machines and re-introduced to the patient. Results were demonstrated in a trial involving 65 patients, where the remission rate was 83% within 3 months.

Saar Gill, MD, PhD

The MPN Research Foundation asked immunotherapy specialist Saar I Gill, MD, PhD, Assistant Professor of Medicine at the Hospital of the University of Pennsylvania (Right) about CAR T and other immunotherapies as prospects for the MPN community. MPNRF is currently funding several projects related to immunotherapy, and it is the focus of the keynote of our MPN Roundtable this autumn. As drivers of research, we feel it is our mission to make sure this is explored as an option sooner rather than later. Dr. Gill has served on several of our grant review panels to assist us in evaluating applicants, especially as they relate to immunotherapy. 

MPNRF: Do you know of anyone doing this kind of research in MPN now? 

SG: There are several groups that are working on CAR T cells for myeloid neoplasms. So far most of the activity has been focused on acute myeloid leukemia because of its higher prevalence and worse short-term prognosis.

To understand the difficulty of making CAR T cell therapy successful for myeloid diseases such as MPN, one must realize that all successful CAR T cell trials to date have targeted “lineage-specific antigens” rather than cancer-specific antigens. Lineage specific antigens are shared between normal and cancerous cells arising from the same lineage. For example, cancerous B cells cause B-cell acute lymphoid leukemia but continue to share most of their surface markers with immature normal B cells. The newly approved product Kymriah induces the patient's’ T cells to attack their cancerous and normal B cells at the same time. It turns out that human beings can live without their B cells for a very long time indeed. If this were not so, CART cell therapies such as Kymriah (Novartis) would be much more toxic.

Now think about myeloid neoplasms. If CAR T cells were to target myeloid antigens indiscriminately, both abnormal and normal myeloid cells would be killed. We cannot live without myeloid cells for long, since they produce the red blood cells that we need to carry oxygen, platelets for blood clotting, and the white blood cells that we need to fight off infection.

To my knowledge, there are no truly specific antigens on the surface of the abnormal cells in patients with myeloid neoplasms. While there are certainly cancer-specific mutations, virtually all of these encode proteins that are inside the cell rather than on its surface, and hence are invisible to CAR T cells.

MPNRF: What are the material differences between a neo-antigen specific cancer vaccine, T-Cell Receptor (TCR) therapy, and CAR-T therapy?  Which have the best prospects for MPNs and why?

SG: All have their problems. While neoantigen-specific cancer vaccines and TCR therapy can target intracellular antigens, the first is limited by immunological response (i.e. responses in blood test) with poor clinical responses (i.e. responses that can actually be seen in the patient), meaning that despite decades of trying, there have been no successful cancer vaccines. The latter is limited in part by the fact that each TCR only recognizes the mutated protein in a given HLA molecule (the lock-and-key mechanism of antigen presentation on HLA molecules means that different products would have to be made for different HLA types. HLA types differ between people and across ethnicities and the most common HLA type in Caucasian, HLA-A0201, is only present in about 30% of Caucasians.

I still think CAR T cell therapy could work for MPNs but this is predicated on either (1) finding a specific cell-surface antigen on MPN, or (2) targeting all myeloid cells but finding a way to protect the normal myeloid cells from attack while leaving the abnormal myeloid cells susceptible to T cell attack.

MPNRF: Is the CALR mutation a "unique" target because of its location on the cell surface as compared to MPL and JAK2 mutations which are inside cells?  How can we take advantage of any unique features of this mutation?

SG: There is great potential for the CALR mutation to be used as a target for CAR T cells, but first we must develop an antibody that is truly specific for the mutant portion of the CALR protein where it is located on the surface of the cell.

MPNRF: The biggest question of all: In the coming years and decades, is it possible or even likely that the abovce mentioned therapy approaches could be included as curative therapies along with Stem Cell transplant?

SG: I think it is possible. There are many avenues of immunotherapy that will converge, and one or more of these should work for MPNs. If cells are alive, they can be killed. It’s just a matter of finding the approach that does this with an adequate therapeutic window (ie. not too toxic to surrounding normal cells).

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