Cancer kills without discrimination to wealth, gender, age, nor ethnicity. However, while rates are increasing primarily due to longevity increases
and environmental factors, great strides have been made in the understanding and treatment of this horrible disease. As I've studied, I have gained
insights that give me hope that we will soon be winning the battle.
Adoptive Cell Therapy; Chimeric Antigen Receptors
Imagine a person with Stage IV Chronic Lymphocytic Leukemia, a cancer of the white blood cells. A scan of his bone marrow shows almost complete replacement
of healthy cells with cancerous. The cancer is chemorefractory, meaning it survives every dose even while his normal rapidly dividing cells do not. Now,
instead of the normal treatment progression and a poor prognosis, some healthy T cells are extracted from his blood. They are processed, induced to replicate,
and then the large resulting colony of cells is infused back into his blood. Thirty days later, a scan reveals his bone marrow to be clear of the cancer and
another 6 months later shows the same; a complete resolution to the cancer.
Read on...
Chimeric Antigen Receptor: Target erbB2
The process of tuning cytotoxic T lymphocytes (CTL) to kill cancer cells is undoubtedly a spectacular innovation but it can be precarious. The primary
function of a CTL is to bind and kill any cell found bearing the ligand of the CTL’s antigen receptor (the CAR in this case) on its membrane. There are
many factors that must be addressed when tailoring the therapy to treat a given pathology; the most significant of which is selecting the CAR’s ligand
(its target). Other factors include how many CAR+ T cells should be injected and how to control their proliferation and longevity after injection. After
completing the reading that went into this post I am not certain that, one, erbB-2 is a suitable CAR target, and two, I have been convinced that the use
of chemotherapy as a neoadjuvant (administered just prior) to any targeted molecular therapy should be questioned.
Read on...
Intracellular Caspase-Modulating Chimeric Antigen Receptor
The Chimeric Antigen Receptor (CAR), first devised by Gross et al in 1989 (1), has proven effective against cancer and holds promise for other therapeutic
applications. Landmark work done by Carl June M.D. et al. led to a recent clinical trial in which CD-19 specific-CAR transfected autologous T cells were
reinfused into a patient with chemorefractory Chronic Lymphoid Leukemia (CLL). This patient, along with another in the same trial, achieved a complete
response within 30 days and remained in remission 10 months after treatment. A specific immune system response was detected and memory effector cells were
generated. The only high level toxic events were Tumor Lysis Syndrome and Hypogammaglobulinemia the later expected as the CAR was specific for CD19 which
is expressed on all early B cells (2). The historical significance of Dr. June’s work notwithstanding, a limitation to this approach exists stemming from
the fact that the peptide containing the epitope targeted by the CAR’s variable region must exist on the surface of the tumor cells. With the exception of
hematopoietic cells, as exemplified in Dr. June’s work, the peptide would preferentially be expressed only on tumor cells so off-tissue toxicity could be
avoided. Unfortunately, this has already occurred during another CAR in which the specificity was set for erbB-2. ErbB-2 is expressed on breast and colon
cancer cells, but it is also found on healthy endothelial cells; one patient died just days after treatment and on-target/off-tissue events were postulated
as the root cause of death (3).
Read on...