A revolutionary new shift in cancer research, dubbed ‘potentially paradigm changing’ has occurred with the first FDA approved gene therapy: CAR-T. It is radical in its culmination of both immunotherapy and gene therapy through the modification of T-cells. Before CAR-T, cancer research had largely focused on disabling cancer cells from the outside, an impractical, imprecise and dangerous method. However, oncology has finally caught up to the genetic revolution with a therapy that eliminates from the inside and has incredibly specific targets.
Practically, how does CAR-T function? Why is it such a vast improvement from chemotherapies and harmful radiation? CAR-T is a one-time infusion of cells and the effects have the duration of a lifetime because unlike chemotherapy, this therapy inserts permanent instructions on how to defeat haematological cancers. As one oncologist said: ”I am not treating you, you are treating you.”
The manufacturing of CAR-T cells requires, firstly, that T-cells (a type of white blood cell) are extracted from a patient. A virus is then used to insert the specific genes that will allow for the production of chimeric antigens on the T-cell surface. These new cells, now the CAR-T cells, are placed in a nutrient broth until they have multiplied into the millions. At this point, they are infused back into the patient and the chimeric antigen receptors are able to attach to MHC complexes on the surface of cancer cells, targeting and killing them. The beauty of CAR-T is that the cells remain in the bloodstream stream for some time, preventing the cancer from returning. It is also important to mention that chemotherapy is additionally used after the removal of white blood cells from the patients in order to make room for the multiplied CAR-T cells.
The success of this therapy began with a three-person trial in Maryland and was funded only by philanthropic support in 2009. After posting results in the New England Journal of Medicine of a patient on the brink of death making a full recovery (Bill Ludwig), investors flooded n and new trials arose. Fast forward from 2009 to 2017 where there is 5% response rate on the complete disappearance of B-Cell lymphoma. There’s a good reason why just months earlier the Oncologic Drugs Advisory Committee voted unanimously in favour of Kymriah, a brand of this cell therapy. Cure is a dreaded word for oncologists who tend to be as pessimistic as possible to prevent the inevitable disappointment of their patients but this was looking promising. No other cancer treatment had brought patients from almost touching pearly white gates due to the tumour having almost swallowed them entirely to a state where bone marrow biopsies were clear.
Although the therapy is radical and largely effective, having an 80% success rate in patients with aggressive leukaemia or lymphoma, most of the late stage drug trials such as the Zuma-1 trial were done with patient with no other health complications. The original trial had 75 children and adults with just one type of leukaemia – B-Cell acute lymphoblastic leukaemia and 81% had no sign of cancer after 3 months. Bringing this therapy into the reality of a hospital room filled with elderly patients with degenerative mind diseases, patients with HIV or an autoimmune disorder, patients with heart problems, etc has led to the numerous issues with this therapy that had previously been bowdlerised by the trials, exposed in the horrifying bright hospital lights.
Half of all patients that have taken this infusion of CART have developed Cytokine release syndrome as a result of the hyperactivity of T-cells being a result of both antibodies and cosmilatology signals in one construct simply meaning the efficacy of CART is directly related to higher amounts of cytokine. CRS is the collateral damage of the immune system being on such high alert since activated T-cells produce cytokines which then produce more immune cells. This means the therapy feels as if gasoline has been poured onto an emerging flame. CRS can lead to fevers and multi-organ failure of the kidneys, heart and liver. As a result, cytokine blockers such as tocilizumab have had to be used in combination with steroids to calm the immune system.
However, an even more terrifying side-affect has become apparent: neurotoxicity caused by a breakdown down of the blood brain barrier. The most horrifying aspect of this is how impossible the neurological issues are to predict; some patients spoke gibberish, others stopped talking, an even unluckier few could not interact at all, unable to respond to the most basic commands. There is still no cure for this, only the hope that such symptoms will alleviate. Unfortunately, in the 1% of patients permanent brain damage ensues.
Alas, as with other precocious cancer cures, large challenges still need to be hurdled before the therapy can reach its full potential. One such challenge we have already mentioned is the drug’s efficacy being directly related to the higher amounts of cytokine produced. To alleviate CSR, natural pathways must be used to separate cytokine production from the hyperactivity of T-Cells. But another huge issue we still have not touched upon is the fact that CAR-T is largely limited to haematological cancers such as leukaemia because T-Cells can only work on smaller scales and within the bloodstream stream cancer cells tend to be more fluid. Finding the cure to ‘cancer’ is a very misleading phrase because while it may be one word, it is not one disease.
Another challenge is yet again resistance. If a cancer cell adapts to change its antigens so different peptides or major histocompatibility complexes are produced on the surface of the cancer than the CAR-T cells still within the patient’s bloodstream are deemed absolutely useless. Data from the trials only followed up after a few months but, after a few years, relapses have been shown to occur. If this is the case, then quite possibly this isn’t the magic bullet to haematological cancers that leukaemia patients have been dying for.
What is the next step then? We must discover a way to genetically engineer gluttonous macrophages instead of T-Cells in order to engulf solid tumours in organs as opposed to just floating clusters. But before moving on to new gene therapies, the neurotoxicity issues caused by CAR-T have led to it still being a last resort for patients with especially aggressive forms of leukaemia or lymphoma. Clearly, CAR-T is still within its foetal stages and requires the researchers of tomorrow to take CAR-T from the nurturing hands of oncologists today and bring it to it’s true potential.
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