Chimeric Antigen Receptor

US-based biopharmaceutical Juno Therapeutics and China-based open-access R&D company, WuXi AppTec, have joined forces in setting up a cell therapy…

If you’re wondering what’s this new CAR that is the subject of a US-China joint venture (and why it’s a very big deal), read on. I’ll try to explain this upcoming very promising but very complex (to understand and undertake) targeted immunotherapy for cancer, transplant and autoimmunity in the following posts.

A therapy that retrains the body’s immune system to fight cancer has provoked excitement after more than 90% of terminally ill patients entered remission.

When this story broke on BBC a couple of months back, it got cancer patients around the world very excited. Indeed, a press conference had to be convened locally to answer the barrage of queries about this “new and revolutionary cancer cure”, of which few details were available, if you read this post.

Coming soon after news that former US President Jimmy Carter was declared “cured” of his metastatic melanoma after treatment with an “immune checkpoint” inhibitor, many doctors (myself included) thought this BBC report was just hyping it up for the same or another checkpoint inhibitor.

As it turned out, it was a different form of cancer immunotherapy called adoptive T-cell transfer, and it apparently “cured” some patients of their leukaemia refractory to conventional chemotherapy.

Adoptive T-cell transfer is not a new therapy: several decades old, in fact. It was such an abject failure that it wasn’t till recent years that the successful advent of checkpoint inhibitors restored Immunotherapy as the rightful fourth column of cancer therapy (the other 3 being surgery, chemotherapy and radiotherapy).

So what’s new (and promising) about adoptive T-cell transfer immunotherapy this time round? Read the next post.

Here’s the principal investigator, Stanley Riddell, shedding more light on the scanty BBC report:

Engineering T Cells for Safe and Effective Cancer Immunotherapy

 Recent advances in understanding the mechanisms by which cancers evade immune recognition have led to new immunotherapies that have the potential to transform the management of many human cancers. T lymphocytes are critical to adaptive immunity to pathogens and tumors because of their longevity and…

It could herald a new era in precision therapies for cancers.
What is adoptive T-cell transfer?
It involves taking out a patent’s tumour, isolating the T-cells within it which would presumably recognise the tumour antigens as “foreign”, boosting the numbers and killing prowess of these T-cells, and then re-injecting them into the patient to (hopefully) wipe off the cancer specifically without doing collateral damage to normal cells.
The reasons why this therapy did not take off in a big way previously are several, including the poor survivability of the re-injected cells, the ability of some cancers to mutate or suppress the expression of the antigen originally recognised, the ability of some cancers to producing immune-suppressing molecules like PD-L1 (now targeted by checkpoint inhibitors), and the high cost and technical difficulty of this highly individualised/personalised treatment.

What is different this time round is the development of CAR: Chimeric Antigen Receptor, made possible with advancements in genetic and protein engineering. What is CAR? Details in the following post.

Artificial T cell receptors (also known as chimeric T cell receptors, chimeric immunoreceptors, chimeric antigen receptors (CARs)) are engineered receptors, which graft an arbitrary specificity onto an immune effector cell. Typically, these receptors are used to graft the specificity of a monoclonal…
This is CAR, a very technical read.
In Greek mythology, a Chimera is a fire-breathing female monster with a lion’s head, a goat’s body, and a serpent’s tail. The imagery is used here to describe an artificial T-cell receptor complex: fusing an antibody-like head & body specifically engineered to recognise and lock-in to the target antigen (could be tumour, MHC molecule, or cytokine), to the tail of the natural T-cell receptor which will set off a chain of intracellular signals which ultimately activates the T-cell to act.

Now, we no longer need to biopan the tumour for reactive T-cells, which may recognise antigens which may not be expressed by all the cancer cells. If we know the specific antigen (or a limited repertoire of antigens) that is universally expressed by all the cancer cells, we can stretch out the 3D protein, analyse the amino acids in the protein chain, work out the corresponding coding DNA sequence, splice the sequence next to the sequence coding for the T-cell receptor “tail” (replacing the native “head & body”), use a viral vector to transfect this chimeric gene into any T-cell, clone and expand the population, and re-introduce this “commando army” into the patient to decimate the cancer.
If this works according to plan, CAR adoptive immunotherapy will be even better than checkpoint inhibitors. Let me explain in the next post.

Our scientists may have uncovered the ‘guidance system’ needed to make cancer immunotherapy more effective.
Immune checkpoint inhibitors “uplift” all activated T-cells generally, either by preventing effector T-cells from committing suicide (blocking PD1-PDL1 interaction: Nivolumab, Pembrolizumab), or by blocking CTLA4 (Ipilimumab), which downregulates T-cell response by mopping up B7 on antigen-presenting cells thus preventing its docking on CD28 to drive T-cells. They ease up on the brakes so that the immune attack can proceed. Because the “easing” is non-specific, autoimmune phenomena constitute the major side-effects of this class of medication.

CAR adoptive immunotherapy, in contrast, is as specific as the synthesized T-cell receptor. Theoretically, this should have less collateral damage to non-targeted cells, although cytokine release syndrome can still be problematic in a violent and unrestrained (albeit targeted) attack. By the same driving a car (pun intended) analogy, this is like stepping on the accelerator: if you floor it, accidents can happen.
Its specificity is also its Achilles heel: you need to determine the specific putative antigen that is not only universally expressed on all the tumour cells, it had better not be on normal cells either.
These 2 arms of cancer immunotherapy can be complementary.
Why am I, a rheumatologist, posting on cancer immunotherapy? This is not the first time, and you may be interested to reference my earlier posts:
Firstly, cancer immunotherapy can and do create autoimmune problems: they are opposite sides of the same coin. As with the checkpoint inhibitors, the inverse aspect, called co-stimulation blockade (Abatacept), is used to wind down excessive immune reactions as seen in diseases like Rheumatoid Arthritis, Lupus and Vasculitis. More relevantly, CAR adoptive immunotherapy can be tweaked to treat autoimmune diseases and prevent transplant rejection as well. More on this in the next and final post (for today).

A gene therapy has been developed that programs a type of immune cell called T regulatory cells (Tregs) to protect transplanted tissues from rejection by the patient’s immune system, report scientists.

The beauty of a build-to-order system like CAR is the flexibility for customisation. The clinical effect can be varied depending on the antigen the artificial receptor is designed to target, as well as the function of the T-cell that is activated.

If, instead of a cytotoxic T-cell or a Natural Killer T-cell, I activate a regulatory T-cell, I can expand the clone army to treat autoimmune diseases and to prevent transplant rejections, as in this paper. I can even pair a cytotoxic-T or NKT to treat such conditions, provided I pair them to receptors that recognise and neutralize specific pro-inflammatory cytokines and reactive immune cells.

The key is in the targeted antigen. For autoimmune diseases, those with specific or narrow repertoire autoantigens or pathogenic autoantibodies will be less laborious to target, like Domain I of beta-2-glycoprotein-I in the Anti-Phospholipid Syndrome, or thyroid autoantibodies in autoimmune thyroid diseases. In such cases, I can fashion the synthetic T-cell receptor to mimic the putative antigen, and pair it to a cytotoxic-T or NKT to knock off the B-cells which express the corresponding autoantibody on their cell surface. Or I can pair the autoantibody to a Treg to immunomodulate the tissue microenvironment of where the putative antigen resides. For transplant, the engineering will be around the Major Histocompatibility Complex (MHC/HLA) antigens, such that patients no longer need to take anti-rejection drugs lifelong. The main inflammatory cytokine in autoimmune diseases can also be targeted if there is no putative antigen or pathogenic autoantibody, such that patients may no longer need to constantly inject themselves with costly anti-cytokine biologics.

The possibilities are quite open to the imagination.

So why didn’t Singapore’s GIC or Temasek, with all the much vaunted bioengineering infrastructure, beat WuXi AppTec in partnering Juno Therapeutics?