CAR T-cell therapy cancer
3d render of the interaction between a CAR T cell and a cancer cell 2048 x 1536 (iStock)

CAR (Chimeric Antigen Receptor) T-cell therapy is a cancer treatment that is making headlines. In fact, it is now on the road to being one of the most promising treatments in oncology. Research results presented at the recent American Society of Clinical Oncology (ASCO) meetings have made it clear that there is much to be excited about.

In a throwback to Henry Ford’s Model T, this medical innovation is called CAR T-cell therapy. It is a type of cellular immunotherapy involves physicians extracting a particular type of white blood cell from the patient’s blood (T-cells) and then attaching them to one of these artificial receptors. Once these cells are infused back into the patient, they recognize cancer cells that contain the particular protein.

CAR T-cell therapy was discovered in1989

This is a cancer therapy that was discovered in 1989 but was not put into high gear until recently. It is already changing how patients with blood cancers that have not been responsive to previous therapy are being treated. Although the technology was described almost three decades ago, clinical implementation did not occur until recently.

Even though CAR T-cell therapy is not well known to the general public, it has been speeding along the medical highway, with no rest stop in sight. 

Treatment for Blood Cancers

The therapy has been FDA approved for patients with particular types of blood cancers that have not been responsive to previous therapy. CAR T-cell therapy has had remarkable success in these relapsed/refractory blood cancers.

Replicating the success in solid tumors (cancers such as lung, breast, mesothelioma, and sarcoma), however, has proved challenging for several reasons. The good news is that recent results from phase I clinical trials (studies that assess the safety of the drug) were recently presented that signal promise.

Related reading: Difficult-to-treat cancers (part 3): Recent advances in the treatment of cancer

In hematological malignancies (blood cancers) the rapid pace is of great value because they are the fourth most common cancer in the United States.  Non-Hodgkins Lymphoma is the most common of these in the United States and outcomes in aggressive and refractory subtypes are poor.

Of this disease, the most common subtype is Diffuse Large B-Cell Lymphoma. Only a small percentage of patients with relapsed disease or disease that was refractory to initial therapy is then cured with a stem cell transplant. Although this treatment has been approved for patients under the age of twenty-five with Acute Lymphoblastic Leukemia until recently this type of therapy had been restricted to smaller clinical trials for other very advanced and aggressive diseases.

Rates of Responses

However, the remarkable rate of responses from these trials caught the eyes of researchers and physicians around the world. These results have shown that patients who had failed conventional therapy were not only seeing their disease stabilize, but also saw a significant response.  Recent trials have shown ongoing complete remission with durations ranging from 18-24 plus months. 

In early trials, there were even persisting CAR T-cells observed in greater than 70% of patients remaining in response at 1 year. Durable responses continued to remain in patients with and without detectable persisting CAR T-cells. 

Although these responses can deepen and improve over time, it has also been seen in instances that the ongoing response of these cells can decrease when a higher amount of tumor burden is present.

Is CAR T-cell therapy right for every patient?

The answer to this question is no. The success of the treatment depends on the individual, their disease, and several other factors.

Plus there are still some side-effects that patients should be aware of before they take this CAR for a spin.  One of them is a condition known as “cytokine storm” or cytokine release syndrome (CRS). About 70-90% of patients may experience this serious reaction to the treatment. Think of it as the radiator breaking down, leading to overheating of your engine with severe flu-like symptoms of fever and body aches. It occurs secondary to the multiplying activity of the T-cells, leading to a dynamic immune response.

Another side effect is known as “CRES” (CAR T-cell Related Encephalopathy Syndrome). It can begin a few days after infusion of the CAR T-cells where patients become confused and disoriented. Think of it as a breakdown in the transmission. You are unable to mentally shift gears and form complex sentences and thoughts that you were able to once before. 

Just like when you take your automobile to a busy shop, it takes a few days for things to be back to normal. These adverse effects are reversible with the right mechanic and a skilled tune-up.

So, why the challenge with solid tumors?

1. Finding the right target

One of these several challenges has been finding the right target to direct the T-cells to attach. Unlike many blood cancers that may have a target, such as CD19, not all solid tumors carry the same antigen. Therefore the CAR may miss targeting some of the cancers.

Recently Memorial Sloan Kettering conducted a clinical trial in which the CAR T-cells targeted mesothelin that is found on solid cancer cells in abundance and less commonly on normal tissue. Mesothelin can be found in mesothelioma, triple negative breast cancer, pancreatic cancer, and lung cancer to name a few.

At Baylor College of Medicine, researchers conducted a trial with CAR T-cells that expressed HER2 receptor to target Sarcomas that did not respond to previous therapy.

2. Bypassing the microenvironment to reach the solid tumor

Another issue has been bypassing the surrounding microenvironment to reach the solid tumor. Many of these cancers produce immune-suppressing molecules such as checkpoint inhibitors PD-L1 (Programmed Death-Ligand 1) which can suppress the T-cell response. 

Conversely, when introduced intravenously to fight blood cancers, engineered CAR T-cells can expand in a robust manner once in the circulation, given an abundance of T-cells in the blood. However, this rapid expansion in the blood is the overactivation of these cells leading to the aforementioned Cytokine Release Syndrome or neurotoxicity.

3. Delivery of the CAR T-cells

A third major issue has been the delivery of the CAR T-cells. In liquid (blood tumors) cells are administered back into the body in the bloodstream where they are able to circulate and seek out and destroy the cancer cells. This has shown to be effective in blood cancers as the CAR T cells are able to readily access the cancerous B-cells. 

In previous studies of solid tumors when CAR T-cells were administered intravenously in the blood, the number of them that actually got into the tumor itself was very small. It is significantly more difficult for the T-cells to infiltrate thousands of layers in a solid mass.

While some trials have aimed to improve the efficacy of the CAR T-cells when administered intravenously, there are other aforementioned ones that involve injecting these cells directly into the tumor or pleural space, at the site, to have more direct access. The City of Hope has established a dual-catheter protocol in which CAR T-cells are injected at both the site of the tumor as well as in a ventricle for specific brain tumors.

Related reading: Difficult-to-treat cancers (part 2): Drug discovery

More Studies

There have now been several Universities and Medical Centers that have been conducting trials with CAR T-cell therapy in solid tumors with the hopes of finding the optimal manner in which to use this treatment. Although it has not achieved the same success as in its treatment with blood cancers, identifying the challenges and making efforts towards bypassing these is a big first step in reaching this new goal.

Related Content:  Technologies That Will Transform Cancer Diagnosis and Treatment

Conclusion

Cancer treatment continues to evolve at a rapid pace with no end in sight.  It is a very exciting time and although the road may not always be straight, it is gratifying to see it continuing for many miles ahead.

 

Joshua Mansour, M.D.
Dr. Joshua Mansour is a board-certified hematologist/oncologist working and in the field of hematopoietic stem cell transplantation and cellular immunotherapy in Stanford, California. In June 2019 he was a recipient of the ‘40 Under 40 in Cancer’ award. Abstracts, manuscripts and commentaries by Dr. Mansour have been published in more than 100 esteemed journals and media outlets including US News & World Report, Canada Free Press, Today’s Practitioner, Physician’s News, and KevinMD. He has given countless presentations at conferences and other institutions, and he has helped design and implement clinical studies to evaluate current treatment plans, collaborated on grant proposals and multi-institutional retrospective studies that have been published. Recently Joshua Mansour. M.D. was featured on Fox Television.

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