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Video Essay Transcript:

Have you ever imagined engineered cell-soldiers fighting tumors inside patients’ bodies? Now, this is no longer a creative dream!

A group of researchers led by Mythili Koneru at Memorial Sloan-Kettering Cancer Center have published a paper indicating a successful CAR T cell design. Through examination, the cells reveal profound tumor eliminating potency on mice models with simulated human ovarian cancer. The success might bring invaluable hope to ovarian cancer patients if achieves success in the ongoing phase I clinical trial.

Originally published on Oncoimmunology in March 2015, the study was carried out by researchers Mythili Koneru, Terence J. Purdon, David Spriggs, and Renier J. Brentjens from Department of Medicine of Memorial Sloan-Kettering Cancer Center, New York, and Susmith Koneru from Rutgers School of Public Health, New Jersey.

The study’s main researcher Mythili Koneru is funded by American Society of Clinical Oncology-Young Investigator Award and Milton Endowed Fellowship, which “provides funding to promising investigators to encourage and promote quality research in clinical oncology”(American Society of Clinical Oncology c2021)

As you anticipated, the cell soldier protagonists in the therapy are CAR T cells. CAR T cell therapy is an immune therapy that genetically engineers patients’ T cells, which is a type of immune cells, to fight cancer on a cell-to-cell basis with the addition of the CAR receptor. Since 2017, there have been 5 CAR T therapies available, but only for certain types of blood cancers like Acute Lymphoblastic Leukemia (ALL). On the other hand, ovarian cancer, as the second most common gynecological malignancy in the United States, results in over 13,000 deaths annually (SEER 2021).

Due to its insidious nature, limited screening tools, and nonspecific symptoms (Zhu et al. 2017), many patients are diagnosed at distant stage, also called the late stage, when cancer has spread to distant organs, and thus conventional techniques of treatments wouldn’t work much.  CAR T cell therapy, on the other hand, can still be effective when cancer has spread to other organs.

Beside the successful application of CAR T cell immunotherapy to blood cancers, various designs and experiments have been undertaken, and difficulties in treating solid tumors have been encountered. The difficulties mainly involve the stress from the nearby tumor cells which may deactivate CAR T cells and cause them to miss-target, and the detrimental cell toxicity to other healthy cells (Odunsi 2017). Several auxiliary functions or receptors also have been tried to enhance CAR T cell performance at the site—just like the CAR T cells here designed in the study—and have achieved some progress (Zhu et al. 2017).

For this study, the CAR T cells target the 4H11-28z CAR receptor, which is an artificial receptor that is proved by previous studies that has molecular-precision recognizing ovarian cancer cells (Dharma et al. 2010); the recognized cancer cells are thus killed by the engineered T cell. Further modification of the cell involves the addition of IL-12 secretion function, a stimulatory chemical that acts through multiple mechanisms to enhance T cell function, and potentially overcomes the inhibitory local tumor environment. Moreover, the added EFGRt gene provides a fail-safe mechanism to enable using a “remote control” substance to shut down CAR T cells when severe adverse effects show up. Such design of the CAR T cells in this study would theoretically address difficulties mentioned above with designed safety mechanisms.

If proven successful in mice models and human trials, it could become one of the last resorts that late-stage ovarian cancer patients can seek out.

Using the mice model, the researchers want to test this design of CAR T cells for treating ovarian cancer and measure its overall efficacy both in vitro and in mice models. Specifically, the CAR receptor should accurately locate the ovarian cancer cells; IL-12 secretion at tumor site should boost their anti-tumor activity; the addition of EFGRt gene should trigger cell death when induced.

To validate their hypothesis, The scientists conducted a testing scheme with ascending complexity for analyzing the CAR T cell’s effectiveness. First, the in vitro activity of the engineered T cell’s identification and killing, secretion of IL-12, and induced cell death through activating the EFGRt gene is examined and compared with control groups.

Then, six groups of mice with no manipulation, an irrelevant CAR receptor, and the designed cells with different stages of engineering are separately carried out on mice injected human ovarian cancer cells two weeks earlier. Meanwhile, other groups of experiments carried out four weeks past cancer cell injection are used to study CAR T cells’ efficacy on advanced tumors.

Comparing with various control and comparison groups, the CAR T cells showed significant ability in eradicating normal and advanced human ovarian cancer tumors inside a living mouse, with a high long-term survival rate. Figures from the research represent the success by the high percentage of mice survived while other control and comparison groups exacerbated and died.

As a serious animal trial, the results should be replicable by other researchers for validation. Here the methods section mentioned all the manipulation and viral vectors available for validation by repeating. Nevertheless, due to information release and the nature of the study, several weaknesses might have undermined the research outcome.

First, no group size of the experiment has been released, which would bring speculations about a small, and thus unrepresentative, group size.

Second, the mice model is composed of mice and human ovarian cancer cells, and thus would not perfectly resemble CAR T cells’ in-patient performance.

Third, as the authors themselves mentioned in the report, the possible on-target off-tumor cell toxicity could not be examined by the mice model. This hypothesizes the situation that the CAR T cells may attack healthy human cells that are not present in the mice model.

Lastly, only one type of cancer cell was tested instead of multiple ovarian cancer cell lines, possibly constrained by funding and types of cells available.  To further validate these weaknesses, replications along with clinical trials are necessary with strict safety protocols.

Based on the successful outcome of the CAR T cell design in vitro and in the mice model, the scientists have designed and carried out a Phase I clinical trial (NCT#: 02498912) that enrolled eighteen subjects with ovarian cancer.  The primary estimated completion date is August 2022 (U.S. National Library of Medicine 2015). Due to the remaining possibilities of unexpected severe adverse effects, the demand for clinical trial results is urgent in order to provide a comprehensive understanding of the therapy. If successful, further clinical trials could be carried out and it may actually become one of the newly available, high efficacy therapies efficient even for late stage ovarian cancers. As many patients are diagnosed with ovarian cancer in the late stage with such a high death rate, the new therapy would possibly save countless lives each year worldwide. Due to the partial similarity between solid tumors, experiences obtained from designing this therapy could foster the translation of CAR T therapy to other cancers like prostate and renal cell carcinoma (Odunsi 2017), which would possibly lead us into a new era where cancer would not be as frightening as it is now.

 

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Featured image source:

CAR T cells attacking cancer [digital image of cell animation]. c2021. Memorial Sloan Kettering Cancer Center. [accessed 2021 Sep. 26]. https://www.mskcc.org/timeline/car-t-timeline-progress.

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