Is CAR-T for Cancer the Latest Immunotherapy Breakthrough?

A study published in Nature (Feb. 2, 2022) offers extraordinary promise in the fight against blood-based cancers. Doctors are using the C word (“cure”) to describe CAR-T for cancer. In this paper, they describe two patients with chronic lymphocytic leukemia (CLL). In one case, the patient had pretty much reached the end of the line with standard chemotherapy. The future looked grim. Then he received a CAR-T infusion with the patented treatment called Kymriah (tisagenlecleucel). He is alive 10 years later, defying the odds with a durable remission!

CAR-T for Cancer: A Game Changer?

For decades the foundations of cancer treatment were surgery, chemotherapy and radiation. The goal was to rid the body of cancer and try to keep it away. Sometimes these approaches worked, but far too often the cancer returned.

That is why there has been a great deal of excitement about immunotherapy. The hope was that if oncologists could turn on the body’s own cancer-fighting immune system, lasting cures could be accomplished. The latest advance is CAR-T for cancer.

What Is CAR-T?

Chimeric antigen receptor or (CAR) T cell therapy was only introduced a few years ago. Kymriah was the first CAR-T for cancer treatment approved by the FDA. It got the green light in August of 2017.

Another more technical description for this approach is the “adoptive transfer of T lymphocytes reprogrammed to target tumor cells” (Nature, Feb. 2, 2022). In this therapy, patients with blood cancers such as leukemia or lymphoma have their own T-cells harvested. These cells then undergo laboratory manipulation to produce modified T-cells to recognize and kill the “bad” cancer cells.

CAR-T for Cancer of the Blood: Chronic Lymphocytic Leukemia

The FDA approved Kymriah for the treatment of ALL (acute lymphoblastic leukemia) and DLBCL (diffuse large B-cell lymphoma). It is reserved for patients who have “refractory or relapsed” disease. In other words, these folks have received “standard” treatments for their lymphomas and leukemias but they are no longer working.

What this means is that insurance companies can refuse to pay for CAR-T for cancer if patients have not exhausted all other options. They may also refuse to pay for treatment of CLL (chronic lymphocytic leukemia) or multiple myeloma, even though there are data suggesting that CAR-T would work for these hard-to-treat cancers.

In 2010, two patients with chronic lymphocytic leukemia were treated with CAR-T cells as part of a phase I clinical trial. The researchers now report durable remissions a decade later.

Both patients remain cancer free. What has these investigators especially excited is that the CAR-T cells seemingly evolved to seek out and kill tumor cells that themselves may have changed over time.

In other words, even after a decade these specialized cells were found still circulating through the bloodstream and acting as scouts on sentinel duty. Doctors speculate that if cancer cells were to show up, the evolved CAR-T cells would recognize them as invaders and attack.

The History of Immunotherapy?

We first started researching immunotherapy against cancer in the 1980s. Back then most cancer researchers were dismissive of this approach.

We had heard about Dr. William Coley, a cancer surgeon who was a pioneer in this field at the turn of the 20th century. Dr. Edward McCarthy is a pathologist at The Johns Hopkins Hospital. He has called Dr. Coley “The Father of Immunotherapy.”

Dr. McCarthy summarized Dr. Coley’s research in the Iowa Orthopaedic Journal (Vol. 26, 2006):

“In 1891, William B. Coley injected streptococcal organisms into a patient with inoperable cancer. He thought that the infection he produced would have the side effect of shrinking the malignant tumor. He was successful, and this was one of the first examples of immunotherapy. Over the next forty years, as head of the Bone Tumor Service at Memorial Hospital in New York, Coley injected more than 1000 cancer patients with bacteria or bacterial products. These products became known as Coley’s Toxins. He and other doctors who used them reported excellent results, especially in bone and soft-tissue sarcomas.

“Despite his reported good results, Coley’s Toxins came under a great deal of criticism because many doctors did not believe his results. This criticism, along with the development of radiation therapy and chemotherapy, caused Coley’s Toxins to gradually disappear from use. However, the modern science of immunology has shown that Coley’s principles were correct and that some cancers are sensitive to an enhanced immune system.”

Dr. William Coley–Too Far Ahead:

Dr. Coley was way ahead of his time. He almost certainly did not understand the precise mechanism whereby he turned on the body’s immune system to attack cancer. But when he exposed patients to bacterial toxins, their immune system went into overdrive. A high fever often accompanied the induced infection. Dr. Coley actually monitored the progress of this treatment by the elevation in body temperature.

Even though he many not have completely understood how his toxin treatment stimulated the immune system, he knew that many patients survived what would have otherwise been a lethal bone or soft tissue sarcoma. His track record was impressive, even by today’s standards. Sadly, “modern” medicine pretty much ignored his experiments and the concepts behind his treatment. 100 years later, cancer researchers are rediscovering immunotherapy.

Modern Day Immunotherapy:

After decades of neglect, modern day cancer researchers have hopped on the immunotherapy bandwagon. No doubt you have seen commercials for Opdivo (nivolumab). This drug is advertised as a “chance to live longer” for patients with a special kind of lung cancer:

“Opdivo works with your immune system.”

It has also been approved by the FDA for metastatic melanoma, advanced renal cell carcinoma, hepatocellular carcinoma, and several other advanced cancers.

Keytruda (pembrolizumab) is another immunotherapy treatment for “advanced non-small cell lung cancer.” It is also approved for classical Hodgkin lymphoma, advanced melanoma, head and neck squamous cell cancer and advanced urothelial bladder cancer.

MABs to the Rescue:

These new immunotherapy drugs are called checkpoint inhibitors. They are monoclonal antibodies (hence “mab” at the end of the generic name). Cancer cells defend themselves against our immune systems by creating checkpoints. The hope is that by inhibiting the checkpoints, the immune system will go after the cancer cells.

The Downside of Boosting the Immune System:

Here’s the rub. When you supercharge the immune system in a blunderbuss kind of way, it can turn into the sorcerer’s apprentice. If you remember the story, the sorcerer leaves his apprentice in charge of the workshop. One of the chores was to bring water in a pail. The apprentice has a few magic spells under his belt and uses one to get a broom to fetch water.

The problem arises when the broom cannot be stopped. When the broom is attacked by the apprentice it just divides and makes more brooms which in turn fetch more water. Soon there is too much water in the workshop and the apprentice panics. The poem ends with a kind of admonition to be careful about summoning assistance that cannot be controlled.

That can happen with monoclonal antibodies. They not only impact cancer cells, but the body in general. Over-stimulating the body’s immunological reaction can lead to complications in the digestive tract, lungs, heart, brain, kidneys, thyroid gland, liver, skin and other organs. Symptoms can include exhaustion and fatigue, severe cough, wheezing, difficulty breathing, abdominal pain, diarrhea, itching, skin rash, painful joints, arthritis, coma, seizures or paralysis.

Checkpoint inhibitors cause complications that are quite different from chemotherapy, but no less troublesome. In some cases the adverse reactions can be life threatening. And the costs of drugs like Keytruda and Opdivo are truly mind boggling.

 CAR-T for Cancer:

For the past few years, oncologists have been excited about the prospects for a new type of immunotherapy called CAR-T for cancer. In addition to Kymriah, the FDA has approved Yescarta (axicabtagene ciloleucel) to treat large B-cell lymphoma.

On October 18, 2017 then FDA Commisssioner, Scott Gottlieb, MD, characterized CAR-T for cancer this way:

“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases. In just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer.”

Results on CAR-T for Cancer:

The concept is stunning, and now researchers have results to show that CAR-T is more effective than some other treatments for certain blood cancers. At the American Society for Hematology meeting, three research teams presented their results.

One team focused on multiple myeloma, while the other two were treating large B-cell lymphoma. The treatment is expensive, possibly as much as half a million dollars. You can read more about the cost at this link.

It is also potentially toxic. Cytokine release syndrome or CRS can produce symptoms such as high fever, fatigue, headaches, nausea, vomiting, body aches, rashes, irregular heart rhythms, low blood pressure and breathing difficulties. Other symptoms can include anemia, depressed platelet counts, severe neurological complications and seizures. People may become confused and delirious.

Good News for CAR-T:

Scientists are encouraged, however, that more than half the patients treated in one trial were still alive after more than a year. These were patients who had no other options since they were no longer responding to traditional therapies. Results for Yescarta for B-cell lymphoma were published in the New England Journal of Medicine, Dec. 10, 2017).

Here’s the summary:

“The objective response rate was 82%, and the complete response rate was 54%. With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%.

“…Ongoing durable remissions have been observed in patients at 24 months. These results, combined with the observation of ongoing long-term remissions beyond 4 years in the previous National Cancer Institute study, suggest that axi-cel provides substantial clinical benefit for patients with refractory disease.”

Learn more about CAR-T against B cell lymphoma at this link.

The study published in Nature (Feb. 2, 2022) involved only two patients with CLL. Both were doing great after 10 years. UNfortunately, one of the patients died recently, but as a result of COVID-19, not cancer.

Not all CLL patients respond so well, though. Only about 20% to 30% go into remission with CAR-T for cancer. And some eventually develop recurrence of their blood cancer. No one yet understands why some cancer patients do so well and others relapse.

It remains to be seen if CAR-T for cancer will extend beyond blood-based cancers like ALL, CLL, B-cell lymphomas and multiple myeloma. So far, this therapy has not proved especially effective against solid tumors. That said, researchers are looking into hard-to-treat breast cancer, colorectal cancers and prostate cancer. New generation CAR-T treatments may crack the code.