Background information

Professor Carl H. June of the University of Pennsylvania is recognized as a pioneer in the CAR-T field. In the latest issue of Nature, the team led by him announced a major discovery: a patient with chronic lymphocytic leukemia (CLL) treated with CAR-T therapy has been cancer free for 5 years. More importantly, the study found that the minimum dose required for CAR-T therapy to exert anticancer effects is only 1 cell!

The paper, titled "Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells," reported that a patient with CLL who received a special CAR-T cell therapy in 2013 have been alleviated, and in the next 5 years, the patient has remained "no cancer" because of a special CAR-T cell and their "progeny" from massive proliferation. In addition, CAR-T cells are still present in the patient's immune system.

The case: 5 years of relief

As a key representative of revolutionary cancer immunotherapy, CAR-T therapy has shown amazing therapeutic effects in hematological tumors. Briefly, the therapy separates T cells from the patient and transforms the T cells in vitro with a "navigation" that can specifically recognize cancer cells - the chimeric antigen receptor (CAR). That is inserting the CAR gene to allow T cells to express the chimeric antigen receptor, and then amplifying such "modified CAR-T cells" and returning them to the patient to exert a specific anticancer effect.

In 2017, the US FDA has approved CAR-T therapy for the treatment of certain acute lymphoblastic leukemia (ALL) and certain types of non-Hodgkin's lymphoma. However, although 80% of patients with advanced ALL treated with CAR-T cell therapy (Kymriah) showed a significant response in clinical trials, only 26% of patients with advanced CLL responded to this type of therapy.

In general, CLL patients treated with CAR-T therapy require three consecutive injections, and the dose of CAR-T cells is gradually increasing (from 10% to 30% to 60%) to control cytokine release syndrome, CRS, a common side effect associated with CAR-T therapy, including varying degrees of flu-like symptoms, fever, nausea, muscle aches, and ICU-level care in severe cases).

The patient reported in the study received two injections (10% and 30% of the dose); however, after the two injections, the patient did not initially respond to CAR-T therapy until day 50, the patient developed CRS, indicating that CAR-T cells are active and may have anti-tumor effects. After imaging analysis, the result showed that the patient's tumor had become smaller, so the doctor decided to give the patient a third injection (the last 60% of the dose). Excitingly, after that, the patient was relieved and it has lasted for 5 years.

Amazing discovery: the minimum dose is only single cell

What surprised the researchers most was that they found that the CAR-T cells in the patient were from single, original cell. "In essence, this means that the minimum dose required for CAR-T therapy to exert anticancer effects is only 1 cell!" said Dr. Joseph A. Fraietta, the lead author of the paper.

According to the researchers, CAR-T cells used to treat this patient are designed to recognize a protein called CD19 on leukemia cells. To achieve this, scientists used a transgenic virus to randomly insert the genetic code (gene) of the CAR that recognizes the CD19 protein into the patient's DNA.

The analysis showed that in this particular case, the CAR sequence (gene) was inserted into a gene called TET2. TET2 is usually responsible for regulating the formation of blood cells and controlling the growth of these cells. When the TET2 gene is destroyed (that is, after the CAR gene is inserted), the corresponding CAR-T cell will be expanded on a large scale, eventually "destroying" the patient's leukemia.

The doctors who spent several years researching this case thought it was "a series of fortunate events."
“This is the result we have been looking forward to. We know that we can learn a lot from every patient anyway. We also want to understand as much as possible what the patient has experienced and why there is such a reaction.” Professor Carl June concluded.

Another outcome: effective prediction of CAR-T therapy

According the related research, I noted that in addition to this paper on Nature, Professors Carl June, Dr. Melenhorst and Dr. Fraietta also published another research report on CAR-T treatment of CLL a few months ago, in Nature Medicine.

In a study entitled "Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia," they found out why some patients with advanced CLL did not respond to CAR-T cell therapy.

Specifically, the study found that patients with CLL who had a vital, healthier T cell subset before receiving CAR-T cell therapy were able to have partial or complete clinical response to treatment, whereas patients lacking these T cells does not respond to CAR-T therapy.

Analysis showed that these healthier "early memory" T cells are marked by the expression of CD8 and CD27 and the lack of CD45RO. Researchers have validated this feature in a small number of patients and predicted which patients will achieve complete remission with 100% accuracy.

Dr. Fraietta said: "Previous studies have shown that pre-existing T cell quality is associated with poor clinical response. The special feature of our study is the identification of key cell subsets and features. With such a very robust Biomarkers, we can collect blood samples from patients, measure the incidence of such T cell populations, and decide whether to use CAR-T therapy for patients. The ability to screen patients most likely to respond to treatment has a huge Clinical impact, because, in this way, patients who are unlikely to respond to such treatments can seek other options as early as possible."

Author's Bio: 

Creative Animodel provides customized preclinical testing services for your Engineered Chimeric Antigen Receptor T (CAR-T) cells. In cooperation with our CAR-T cells production division, Creative Animodel, we are able to provide you with one-stop full service of both CAR-T production and preclinical testing. We also offer services for customized CAR-T cell toxicity management assessments. We conduct CAR-T cell preclinical studies in human tumor sample derived xenograft mouse/rat models.