In Remission for 10 Years: Long-term Toxicity Data on CAR T Cells

Veronica Hackethal, MD

July 21, 2020

When a patient with cancer hears there isn't much left that doctors can do, it always stays fresh in the mind.

Doug Olson was first diagnosed with chronic lymphocytic leukemia (CLL) over 20 years ago, in 1996. For several years, his doctors used the watch-and-wait approach. But then his cancer progressed and needed treatment. By 2010, it had mutated so much that it no longer responded to standard therapy.

He was rapidly running out of options. Back then, the only treatment left was a bone marrow transplant. Without one, his doctors said, he would have 1 or 2 years left to live.

"I was really trying to avoid a bone marrow transplant. You're playing your last card if that doesn't work. It's a pretty rough procedure," Olson told Medscape Medical News.

Looking back, Olson counts himself as lucky — for being in the right place, at the right time, with the right doctor. His oncologist was David Porter, MD, the principal investigator on a trial at the University of Pennsylvania that was investigating a brand new approach to treating cancer: chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell therapy uses a patient's own T cells engineered to express a receptor that targets proteins on cancer cells. CAR T cells are considered "living drugs" because they expand inside the body and stick around for years — maybe for a lifetime — to fight the cancer if it tries to come back.

"I was certainly intrigued by the approach. It had worked in mice, and it was the sort of thing that looked like it would work," Olson recalled.

Science is not a foreign language to Olson. He holds a PhD in medicinal chemistry, spent most of his career in the in vitro diagnostics industry, and currently acts as chief executive officer of Buhlmann Diagnostics Corp.

So he read the clinical protocol for the first in-human trial of CAR T cells and agreed to become patient number two.

Olson's T cells were harvested, engineered to attack the CD19 antigen found on malignant and normal B lymphocytes, and then were expanded into millions in the lab. After undergoing preconditioning with chemotherapy to minimize rejection and boost the CAR T cells' expansion inside the body, he received several infusions of the new therapy over the course of 3 days.

Nothing really happened for 2 weeks. Then he developed severe flu-like symptoms — so bad that he was hospitalized.

Ironically, getting sick was a sign that the CAR T cells were working. Olson was experiencing one of the main short-term effects of CAR T-cell therapy: cytokine release syndrome. Symptoms include extremely high fevers and dangerous drops in blood pressure that can potentially cause end-organ damage.

In the early trials of these products, some patients experienced such a severe reaction that they needed intensive care, and some died. With increasing clinical experience, doctors have learned to control the reaction with the use of steroids and interleukein-6 inhibitors such as tocilizumab (Actemra).

Fortunately for Olson, the reaction passed, and he was eventually discharged.

Then the "aha moment" happened. Four weeks after receiving the CAR T cells, Olson found out that he was cancer free.

"It still gives me shivers," he said. "Dr Porter said, 'Your bone marrow's completely free. We just can't find a cancer cell anywhere.' "

The remission has lasted, and it is now 10 years later.

Balancing Long-term Risks vs Benefits

Long-term data have been accumulating for these novel therapies since Olson's treatment in 2010. This is particularly important for CAR T-cell therapy, because of its longevity. Because these are living cells and are expected to persist in the body for years, there is great interest in longer-term data, especially the risks for toxicity.

The FDA requires clinical follow-up for at least 15 years for patients treated with CAR T-cell therapy or any other genetically modified cells.

So far, most of the experience with CAR T cells comes from anti-CD19-directed therapy, which has shown "remarkable" remission rates in the 50% to 85% range, said Nirali Shah, MD, head of the hematologic malignancies section of the Pediatric Oncology Branch at the National Cancer Institute (NCI).

The most recent results presented at this year's annual meeting of the American Society of Clinical Oncology support earlier efficacy data, she noted. In the longest follow-up to date, researchers reported remissions lasting over 9 years in patients with relapsed/refractory B-cell lymphoma or CLL treated with Kite's axicaptagene cilleucel (Yescarta), one of two anti-CD19-directed CAR T-cell therapies approved by the FDA in 2017 (the other is Novartis' tisagenlecleucel [Kymriah]).

This study included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved in 54% of patients, and 22% had partial remission.

The other focus is long-term safety. Although some of the long-term adverse effects are known and are manageable, others fall into the theoretical realm. In early May 2020, the NCI held a multidisciplinary virtual conference on CAR T-cell therapy "to encourage collaborative research about the subacute and potentially long-term toxicity profile of these treatments."

"We know just a little at this point about late- and long-term effects of CAR-T therapy, because we are relatively early in the era of CAR T cells," said Merav Bar, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.

B-cell Aplasia and Risk for New Infections

What is known is that B-cell aplasia represents the most common long-term adverse effect of CAR T-cell therapy. B-cell aplasia results when anti-CD19 CAR-T therapy wipes out healthy B cells as well as the malignant ones responsible for leukemia/lymphoma.

As major players in the immune system, B cells are a key defense against viruses. So B-cell aplasia represents a very specific type of immunosuppression. It is generally less severe than immunosuppression that occurs after organ transplant, which hits the immune system pretty much across the board and carries a much higher risk for infection.

The main concern is what happens when someone with B-cell aplasia encounters a new pathogen, such as SARS-CoV-2.

After infection, B cells generate memory cells, which are not killed off by anti-CD19 therapy and that stick around for life. So a patient such as Olson would still make antibodies that fight infections they experienced before receiving CAR-T therapy, such as childhood chickenpox. But now they are unable to make new memory cells, so these patients receive monthly immunoglobulin infusions to protect against pathogens they have not previously encountered.

Olson takes this in stride and says he isn't overly worried about COVID-19. He follows the recommended precautions for a man his age. He wears a mask, washes his hands frequently, and tries to maintain social distancing. But he doesn't stay locked up in his New Hampshire home.

"I took the attitude when I was diagnosed with cancer that I'm going to live my life," he said. "Quality of life to me is more important than quantity."

Neuropsychiatric Toxicity

Another problem is the possibility of neuropsychiatric toxicity. Past studies have reported a wide range of such toxicities associated with CAR T-cell therapy, including seizures and hallucinations. Most have occurred early in the course of treatment and appear to be short-lived and reversible. However, there remain questions about long-term neuropsychiatric problems.

In a long-term study of 40 patients with relapsed/refractory CLL, non-Hodgkin lymphoma, and ALL, nearly half of patients (47.5%, 19/40) self-reported at least one clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty) 1 to 5 years after anti-CD19 CAR T-cell therapy. In addition, 37.5% (15/40) self-reported cognitive difficulties.

"Patients with more severe neurotoxicity showed a trend for more cognitive difficulties afterwards," said Bar, senior author of the study.

However, teasing out the role that CAR T-cell therapy plays in these problems poses a challenge. All of these patients had been heavily pretreated with previous cancer therapy, which has also been associated with neuropsychiatric problems.

"So far, we don't know what caused it," Bar said. "Nevertheless, people need to pay attention to neuropsychiatric symptoms in CAR T-cell therapy. It is important to continue to monitor these patients for these issues."

Graft-vs-Host Disease

Another potential problem is graft-vs-host disease (GVHD). This is not uncommon after hematopoietic stem cell transplants. It develops when the donor T cells view antigens on healthy recipient cells as foreign and attack them.

For patients who are treated with CAR T cells, GVHD is mostly a concern among individuals who have previously had a transplant and who are already at increased risk for it.

In a study of late effects among 86 adults treated with anti-CD19 CAR T cells for relapsed/refractory non-Hodgkin lymphoma, Bar and colleagues found that GVHD occurred only among patients who had received a previous donor stem cell transplant. Of these, 20% (3/15) developed GVHD about 28 months after CAR-T therapy.

"The data for CAR T cells causing GVHD really hasn't shown that it's a huge problem, although we have seen it and are continuing to monitor for it," the NCI's Shah commented to Medscape Medical News.

Other Long-term Adverse Effects

A range of other long-term adverse effects have been reported with CAR-T therapy, including prolonged cytopenias (reduced mature blood cells), myelodysplasia (bone marrow failure), and second malignancies.

In the study with the longest follow-up to date, 16% (7/43) of patients developed second malignancies, which is comparable to data from Bar's study in Seattle (15%, 13/86). The researchers in this study consider this rate to be no higher than expected: these patients had already received extensive chemotherapy, which increases the risk for other cancers, they point out.

However, this brings up theoretical concerns about the long-term effects of gene modification. CAR T cells are engineered using retroviruses (mainly lentiviruses), which randomly insert the CAR genes into the host genome. Doing so may cause mutations that could promote cancer. These lentiviruses also carry the theoretical risk of becoming capable of viral replication once inside the body.

To address these concerns, viruses used to engineer CAR T cells go through comprehensive safety testing. After therapy, patients are checked every few months during the first year and annually after that.

So far, there have been no reports of cancers associated with CAR T-cell therapy.

"Any type of cancer is a very theoretical risk," Bar told Medscape Medical News. "Most likely the malignancies in our study were related to prior treatment that the patients received. None of them had any evidence of replication-competent lentivirus, or any other evidence that the malignancies were related to the CAR T cells."

Another theoretical concern is the possibility of new-onset autoimmune disease, although, once again, no cases have been reported so far.

"We think of it as a theoretic possibility. Whenever you jack up the immune system, autoimmune disease is a potential risk," said Carl June, MD, director of the Center for Cellular Immunotherapies at the University of Pennsylvania.

June was the co–principal investigator of the trial in which Olson participated. He is also the inventor on patents for CAR T cells licensed by the University of Pennsylvania to Novartis and Tmunity and is a scientific founder with equity in Tmunity.

Still, autoimmunity could occur, and scientists are looking out for it.

"We are continuing to be vigilant in our monitoring for autoimmune disease," Shah added. "We've been doing CAR T-cell therapy since 2012, and I think we have yet to see true autoimmunity beyond GVHD."

Future Directions

In the 10 years since Olson received CAR T-cell therapy, an entire industry has sprung up. Over 100 companies worldwide are now developing CAR T-cell therapies targeting various antigens. These therapies are directed at about 60 different tumor types, including solid tumors. Nearly 200 clinical trials are underway, though most are still in early stages: as of September 2019, only 5% had reached phase 3.

Clinical data show promising results for CAR T-cell therapy directed against CD22 (overexpressed on ALL cells), and BCMA (found on almost all multiple myeloma cells). Yet questions remain as to whether CAR T cells will be as effective if they target antigens other than CD19 or cells other than B lymphocytes. One of the biggest research questions is whether they will be effective against solid tumors.

One research avenue being watched with great interest is the development of universal CAR T cells. So far, such products are at very early stages of development (phase 1 trials), but they are attractive because of the potential advantages they offer over bespoke CAR T cells. Automating the process holds the promise of immediate availability, standardizing production, expanding access, and lowering costs. And because the T cells for this universal product come from healthy donors, they may function better than T cells that have been battered and bruised by past cancer treatments, or even the cancer itself.

However, precisely because they are developed from healthy donor T cells, universal CAR T cells may pose increased risk for GVHD. Scientists are trying to get around this problem by engineering universal CAR T cells that lack the T-cell receptor involved in GVHD.

There are also other concerns. Nature has a penchant for mutation. Engineering CAR T cells without T-cell receptors means the body may no longer detect or reject a universal CAR T cell if it goes rogue. Also, gene insertion in universal CAR-T therapy is targeted rather than random (as in bespoke CAR T cells), which could create off-target effects. Both issues create a theoretical risk of such products inducing an untreatable CAR T-cell therapy–associated cancer.

"The theoretic risk with universal cells is that their safety profile may not be as good for long term," June commented.

Hope for the Future

From that first trial in which June and Porter used CAR T cells, two of three patients they treated are still alive 10 years later.

Olson is one of these two, and he still undergoes monitoring every 3 months to check for relapse. So far, none of his tests have shown signs of his cancer returning.

After going into remission, Doug spent the next 6 to 9 months regaining his health and strength.

"I figured if I had this amazing treatment that saved my life, I had an obligation to stay alive," he said. "I'd better not die of something like a heart attack!"

He took up long distance running and has completed six half marathons. He became involved in the Leukemia and Lymphoma Society, participating in fund-raising and helping newly diagnosed patients. Over the years, he has also given talks for researchers, people with cancer, and healthcare providers.

Doug is now 73. Today, he marvels at how rapidly the CAR-T field has progressed.

"Twenty years ago, if you had cancer, your prospects weren't nearly as good as these days. In 2010, people still didn't believe in CAR T-cell therapy," he said. "My goal always in telling my story is a message of hope."

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