CAR-T Cell Therapy for Cancer Treatment – An Insight into Side Effects

T-Cells are a part of our immune system. Made in the thymus gland of our bodies, they are white blood cells which constantly clean our system by hunting and attacking any abnormal cells or substances.

Recently, in August 2017, the U.S. Food and Drug Administration (FDA) approved a genetically engineered T cell therapy called – CAR-T cell therapy (chimeric antigen receptor T-cell therapy) – for treatment of B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. This therapy is developed by the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) and the approval was granted to Novartis for the CAR-T cell therapy, Kymriah™. Kymriah is the first therapy based on gene transfer approved by the FDA.

These engineered T-cells have the potential to target a particular protein called CD19 expressed on the cancer cells. This new personalised immunotherapy has been shown to effectively launch attack and kill large number of cancer cells. For each single engineered cell a patients receive, it can generate an army of more than 10,000 “killer” cells.  

Early Clinical trials on CAR-T cell therapy showed that more than 90 percent of patients achieved a complete remission one month after receiving the therapy.  Later, in 2015 global registration trial 68 children and young adults with advanced ALL were treated at 25 centers across the world – 83% of the patients who received this treatment of their own engineered cells achieved a complete remission.

No doubt, this treatment is very effective, but it comes with its own set of mild to severe side effects which arise as a result of the body’s immune response to the treatment. Once the engineered T- cells are injected into a patient’s body, the body launches an immune attack resulting in increase in proteins involved in inflammation. The side effects of CAR-T cell therapy are a double edged sword. It is a necessary and dangerous phenomenon at the same time. If a patient does have the side effect, it’s an indication that the drug won’t be successful in that patient.

Let us understand what these side effects may be:

Cytokine Release Syndrome (CRS): Cytokines are chemical messengers that help the T cells perform their duties. Cytokine-release syndrome is a complex of symptoms associated with the use of many antibodies. In CAR-T cell therapy, when a patient is infused with re-engineered T-cells, they may experience a wide range of symptoms resulting from a massive release of cytokines from cells targeted by these re-engineered T-cells. This phenomenon is sometimes also called “Cytokine storm”. This release of cytokines may manifests as symptoms such as:

  • High fever
  • Nausea
  • Chills
  • Low blood pressure
  • Low heart rate
  • Poor oxygenation
  • Asthenia or general lack of energy
  • Headache
  • Rash
  • Scratchy throat
  • Dyspnea or difficulty breathing
  • Unexpected organ damage
  • Delirium, confusion, seizures

For some patients these may be mild in nature, but some may experience life-threatening reactions. Doctors notice that most severe reactions happen after first infusions. The onset of these symptoms, which are reversible in nature, is typically within the first week of treatment. Elevated levels of markers like serum ferritin (greater than 500,000 ng/mL), IFN-gamma and IL-6 in the body indicate CRS.

Although CRS is the most common reason for hospitalization of a patient being treated with CAR-T cell therapy, it’s occurrence indicates that the therapy is going to show results.

Dr. Carl June, Richard W. Vague Professor in Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, suggests physicians use Actemra (tocilizumab) to reverse the adverse event.

Neurologic toxicities: CAR-T cell therapy may lead to a number of neurological side-effects most of which occur simultaneously or with delayed onset with cytokine release syndrome. However, this response is not completely understood. Manifestations of neurotoxicity may include:

  • Headache
  • Aphasia or problems speaking,
  • Decrease in consciousness
  • Delirium and Hallucinations
  • Seizures
  • Coma

Dr. Carl June says that neurotoxicities are not associated with response rates, unlike cytokine release syndrome which is associated with positive response rates.

Results of a clinical trial done on 133 patients by a team lead by Dr. Cameron Turtle, published in AACR Journal in 2017, showed that patients having endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. He found that patients with severe neurotoxicity had disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier (BBB) permeability, which allowed leakage of cytokines into the cerebrospinal fluid. The team found that the most common type of neurologic side effect was delirium with maintained alertness which was seen in 35 patients in this trial.

The team identified 2 main occurrences in a patient within 36 hrs after CAR-T cell infusion, that would predict with high accuracy that a patient would experience life-threatening neurotoxic side effects:  

  • Fever of at least 102 degrees Fahrenheit
  • High levels of two cytokines (IL-6 and MCP-1)

Scientists do not know the the best treatment for neurologic toxicities of CAR-T cell therapy yet. More research on the causes and treatments of these toxicities is being planned.

Loss of normal B cells (B cell aplasia): Since the CD19 protein that CAR-T cells target is found on the surface of both cancerous as well as normal cells, CAR-T cell therapy not only destroys cancerous B cells but also normal B cells. This results in depletion of number of normal B cells, also called B cell aplasia. Normally, B cells produce antibodies to fight against infections. So the lack of B cells manifests as:

  • Less ability to fight against infections
  • Increased occurrence of bacterial and viral infections such as respiratory infections, skin infections, GI infections etc.

Although the duration for which B cell aplasia persists is not known, no long-term side effects have been noted. Intravenous immunoglobulin replacement is used to prevent infections.

Tumor Lysis Syndrome (TLS): When cancer cells die and breakdown they release substances in the blood. When the kidney is not able to clear these substances from the blood, their concentration continues to rise, resulting in tumor lysis syndrome. TLS can be a life-threatening complication of any treatment that causes breakdown of cancer cells, including CAR-T cells. It is a group of metabolic complications which include:

  • high levels of Uric acid (hyperuricemia)
  • high levels of Potassium (hyperkalemia)
  • high levels of Phosphate (hyperphosphatemia)
  • low levels of calcium (hypocalcemia)

These manifest as:

  • nausea
  • vomiting
  • diarrhea
  • muscle cramps or twitches
  • weakness
  • numbness or tingling
  • fatigue
  • decreased urination
  • irregular heart rate
  • confusion
  • restlessness
  • irritability
  • delirium
  • hallucinations
  • seizures

TLS usually occurs at the onset of toxic cancer treatments, but may also occur one month or more after CAR-T cell therapy. The complication has been managed by standard supportive therapy depending on the symptoms.

Although these side effects of CAR-T cell therapy and other immunotherapies have been observed in ALL, CLL, diffuse large B-cell lymphoma, multiple myeloma, ovarian cancer, and pancreatic cancer, use of these cell therapies is likely to dramatically increase in the future. Nevertheless, our scientific community has to go a long way to go in terms of understanding the mechanisms and treatment of mainly these side effects, so as to make the CAR-T cell therapy more efficient as a treatment.

 

Dr. Carl H. June, MD, of the University of Pennsylvania, one of the pioneers of CAR-T cell therapy, will share all about his CAR T-Cell Journey and the Cancer Treatment Revolution with CureTalks on November 15, 2017, 1 PM EST. Dr. June, was awarded the 2017 David A. Karnofsky Memorial Award at ASCO 2017, an honor bestowed for his pioneering work on CAR T-cell therapy.

 

 

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