Rose McNulty

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 in patients with non–Hodgkin lymphoma (NHL). 

Given that patients receiving this therapy are surviving longer, the authors feel it's necessary that we better understand the longer-term outcomes associated with this newer therapeutic approach, especially knowing that neurotoxicity and cytokine release syndrome (CRS) are common adverse events often observed in this population.

CAR T-cell therapy has emerged as a revolutionary treatment in certain cancers, including relapsed or refractory hematologic malignancies. With more patents having achieved and maintained durable responses, research on longer term effects of CAR T-cell therapy in survivors is warranted.

The current study examined neurocognitive performance in patients with NHL prior to CAR T-cell therapy conditioning treatment and 30 days, 90 days, and at 1 year post treatment. Patients were eligible regardless of disease response after treatment.

A total of 117 patients with a mean age of 61 years were eligible for the study, and 87% of those patients received axicabtagene ciloleucel while the rest received tisagenlecleucel. Overall, 73% of patients responded to therapy by 90 days after infusion. Of the 54 patients who underwent neurocognitive assessment at 1 year, 71% were still showing disease response.

Neurocognitive assessments were conducted by trained research coordinators or doctoral or postdoctoral trainees in clinical psychology being supervised by a licensed clinical psychologist and neuropsychologist with expertise in assessing patients with cancer.

The overall rate of neurocognitive impairment at baseline was 33%. By day 30, this had risen to 42%, and at day 90, the rate was 48%. However, by day 360, the overall rate had decreased to 35%. The most impaired measures of neurocognitive ability were verbal ability at baseline, immediate verbal memory at day 30 post treatment, verbal ability at day 90, and delayed memory at 1 year post treatment (5%, 7%, 7%, and 4%, respectively). Total neurocognitive performance (TNP) and executive function generally decreased from baseline to day 90 before improving by day 360. There were small but significant linear visuospatial declines throughout the study period.

Demographic and clinical associations with TNP were also examined, although mixed models to assess a selection of variables—including age, gender, education, lines of prior therapy, CRS, neurotoxicity, inpatient days before day 100, and disease response at days 90 and 360—showed no significant associations with change in TNP. Given the lack of association between CRS and TNP, high levels of systemic inflammation may not be a mechanism for worse cognitive function outcomes, the authors note, adding that further research is necessary to confirm this suspicion.

Overall, patients who had undergone fewer than 4 lines of therapy prior to CAR T-cell treatment had slightly better TNP throughout the time points in the study. Additionally, those who experienced grade 2 or above neurotoxicity—but not CRS—performed slightly worse compared with patients with grade 0 or 1 throughout the study, including at baseline. The study authors note the possibility that poorer neurocognition before CAR T-cell therapy may be at a greater risk of neurotoxicity.

The rates of cognitive impairment in patients with NHL undergoing CAR T-cell therapy in this study are similar those in studies of other populations with cancer, and early screening may help identify patients who are at risk of longer-term cognitive impairment after CAR T-cell therapy, the authors concluded.

“Because neurocognitive performance after CAR T-cell therapy could change for a complex variety of reasons, we did not attempt to attribute changes to particular causal factors,” the study authors noted. “Instead, the study is intended to provide information to help educate patients and family members about what to expect after CAR T-cell therapy and identify potential supportive care needs.“

Hoogland AI, Barata A, Logue J, et al. Change in neurocognitive performance among patients with non-Hodgkin's lymphoma in the first year after CAR T-cell therapy. 

. Published online April 1, 2022. doi:10.1016/j.jtct.2022.03.023

Articles

As patients who undergo CAR T-cell therapy survive longer, more research is required into the long-term neurocognitive effects of this treatment. 

New Study Explores Neurocognitive Outcomes Following CAR T-Cell Therapy

Investigators from UNC Lineberger Comprehensive Cancer Center have successfully incorporated an experimental safety switch into 

chimeric antigen receptor (CAR) T-cell therapy

, reducing the severity of the treatment’s side effects in an early-phase trial.1 Their findings, which were published in the American Society of Hematology journal 

demonstrate a proof-of-principle with potential to expand the use of CAR T-cell therapy in conjunction with the safety switch.

 that involves taking T-cells from a patient’s immune system, modifying them to prime them to attack cancer cells, then infusing them back into the patient’s blood, has picked up steam in the treatment of blood cancers since the first options were approved by the FDA in 2017. The results have been stunning, with leukemia and lymphoma patients sometimes experiencing complete remission on CAR T-cell therapy. But like most cancer therapies, it comes with a risk of side effects, some of which can be life-threatening.

Unlike with traditional oral and intravenous cancer drugs that have a dose-toxicity relationship and can be reduced to mitigate treatment toxicity, cell-based immunotherapies cannot be altered once the cells are infused with the patient’s blood. The safety switch developed by UNC Lineberger researchers, called inducible caspase-9, or iC9, is included in the engineered T-cells before infusion and can be activated with the drug rimiducid if toxic side effects develop.

In an ongoing early-phase clinical trial, researchers are working to determine whether a CAR T-cell therapy with the iC9 safety switch is safe and effective In patients with relapsed or refractory B-cell acute lymphoblastic leukemia. One of the participants, a 26-year-old woman, experienced immune effector cell-associated neurotoxicity syndrome, a severe side effect of CAR T-cell therapy. Once physicians administered rimiducid, the safety switch activated and reduced the number of modified T-cells circulating in her blood by almost 60% within 4 hours and 90% within 24 hours, eliminating the toxicities almost entirely in a single day.

"Even though this case study only documents an outcome in one patient, the fact that the drug was so successful so quickly gives us hope that it could have wider applications in a larger group of leukemia patients," said Gianpietro Dotti, MD, director of the UNC Lineberger Cellular Immunotherapy Program and professor of medicine at the UNC School of Medicine. "It should be noted that while rimiducid mitigated her toxicities, it also lowered the number of iC9 T cells fighting her cancer by 90 percent. But there seemed to be sufficient T-cells still circulating to maintain an anticancer response."

Researchers also aim to find out whether lower doses of rimiducid in patients with less severe toxicities might prevent more severe toxicities from occurring. The safety switch also might offer potential for utilizing CAR T-cells to treat solid-tumor cancers, an area where progress has been much slower.

"The ability to use a safety switch may also allow us to treat patients with solid tumors where there may be concern about the CAR-T cells affecting non-cancer tissue," Jonathan Serody, MD, director of the UNC Lineberger Cellular Therapy Program, said. "In those instances, side effects can be eliminated by activating the safety switch."

Matthew Foster, MD, lead author of the study, associate professor in the UNC School of Medicine, and a UNC Lineberger member, sees potential for even more progress in CAR T-cell therapies this year. "Given these results and the well-established high response rates in B-cell acute lymphoblastic leukemia patients receiving CAR-T cells,” he said, “it is reasonable to have a high bar in 2021 and expect that we can achieve both safety and efficacy from such therapies."

Foster MC, Savoldo B, Lau W, et al. Utility of safety switch to abrogate CD19.CAR T cell-associated neurotoxicity. 

Published online February 23, 2021. doi:10.1182/blood.2021010784

An experimental safety switch incorporated into chimeric antigen receptor (CAR) T-cell therapy reduced the severity of the treatment’s side effects in an early-phase trial.

Experimental Safety Switch Has Potential to Reduce CAR T Side Effects

Data gathered by Cardinal Health Specialty Solutions revealed roadblocks community oncology practices encounter when trying to navigate payer approvals for CAR T-cell therapy.

Delays Mean Some Miss Window for CAR T-Cell Therapy, Cardinal Health Data Show

A recent paper in Nature Cancer outlines a novel strategy for overcoming barriers to CAR T-cell therapy in glioblastoma by pretreating the vascular microenvironment.

Moving a Step Closer to Using CAR T-Cell Therapy in Solid Tumors

At the recent meeting of the American Society of Hematology, results from several studies involved the use of chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma. 

Deepu Madduri, MD, Discusses CARTITUDE-1 Data for Multiple Myeloma—and Clinical Trials During COVID-19

Karl Kilgore, PhD, a senior research scientist at Avalere Health, discusses Medicare data that offer insights on the overall costs of CAR T-cell therapy relative to transplants.

Real-World Data Offer Good News for CAR T-Cell Therapy

City of Hope's Dr. Tanya Siddiqi offers an update on a new chimeric antigen receptor (CAR) T-cell therapy awaiting approval from the FDA.

Tanya Siddiqi, MD, Discusses the Promise of Reduced Toxicity With Liso-Cel

Gaining Knowledge of CAR T-Cell Therapy, and CRS, Over Time

The vice president for Clinical Services at OneOncology describes challenges and opportunities for chimeric antigen receptor (CAR) T-cell therapy in the community practice setting.

OneOncology’s Duncan Allen, MHA, Discusses Bringing CAR T-cell Therapy to the Community Setting

From the Academic Center to Community Practice 

CAR-T Spotlight

Genentech today announced that tiragolumab, a novel anti-TIGIT immunotherapy, was granted 

 (BTD) by the FDA for use in combination with atezolizumab (Tecentriq) in the first-line 

treatment of metastatic non-small cell lung cancer

 (NSCLC) patients whose tumors have high levels of PD-L1 and do not have 

 to be granted BTD by the FDA. The designation was based on data from the phase 2 CITYSCAPE trial (

 at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program in May. TIGIT is an immune checkpoint protein that is expressed on multiple immune cells, including T cells.

The double-blind, placebo-controlled trial included 135 chemotherapy-naïve, PD-L1-positive (tumor proportion score [TPS] ≥ 1% determined by 22C3 IHC pharmDx Dako assay) NSCLC patients with locally advanced or metastatic disease and no 

 Primary end points are overall response rate (ORR) and median progression-free survival (PFS).

Patients were randomized to receive either tiragolumab plus atezolizumab (n = 67) or atezolizumab plus a placebo (n = 68), and an initial analysis with median follow-up of 5.9 months found that the tiragolumab cohort had a better ORR and longer median PFS compared with the placebo group. Treatment-related adverse events (TRAEs) occurred in 72% of the placebo group and 80.6% of the tiragolumab cohort. The full results presented at ASCO provided an additional 6 months of follow-up, with a median follow-up of 10.9 months as of December 2, 2020.

ORR and median PFS remained improved in the tiragolumab cohort compared with the placebo group. Tiragolumab-treated patients saw a 37.3% ORR and 5.6-month median PFS versus 20.6% and 3.9 months in patients on the atezolizumab and placebo regimen. In an exploratory analysis of people whose tumors expressed high levels of PD-L1 (TPS ≥ 50%) showed a 66% ORR in the combination therapy group versus 24% with atezolizumab alone. The safety profile remained tolerable with the combination therapy.

The CITYSCAPE trial is the first randomized trial of an anti-TIGIT therapy and provides evidence that targeting both TIGIT and PD-L1 may improve anti-tumor activity by amplifying immune response. Biomarker analyses from the trial will be presented at the International Association for the Study of Lung Cancer 2020 World Conference, which is set for January 28-31, 2021.

“We have been researching TIGIT as a novel cancer immunotherapy target for almost 10 years and we are pleased that the FDA has acknowledged the potential of tiragolumab to substantially improve outcomes for people with certain types of lung cancer,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in a statement. “We look forward to advancing our tiragolumab development program, which includes chemotherapy-free combinations and trials in early stages of disease across multiple cancer types with high unmet need.”

The tiragolumab development program aims to expand into earlier disease stages and new patient populations with unmet needs. There are ongoing randomized trials in metastatic NSCLC and small cell lung cancer; earlier disease stages such as stage III NSCLS and locally advanced esophageal cancer; and in metastatic esophageal squamous cancer and cervical cancer. 

1. Genentech’s Novel Anti-TIGIT Tiragolumab Granted FDA Breakthrough Therapy Designation in Combination With Tecentriq for PD-L1-High Non-Small Cell Lung Cancer. News release. Genentech; January 5, 2021. Accessed January 5, 2021. 

https://www.gene.com/media/press-releases/14892/2021-01-04/genentechs-novel-anti-tigit-tiragolumab-

2. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract 9503.

Genentech's tiragolumab, a novel immunotherapy for non-small cell lung cancer with PD-L1 expression, is the first anti-TIGIT therapy to be granted Breakthrough Therapy Designation.

FDA Grants Tiragolumab Breakthrough Therapy Designation for PD-L1-High NSCLC

More than 3 years after FDA approved the first options in chimeric antigen receptor (CAR) T-cell therapy, Bristol Myers Squibb (BMS) awaits word on whether its investigational treatment, lisocabtagene maraleucel (liso-cel) will be approved. 

, BMS announced that FDA would not meet its target approval date due to the agency’s inability to complete inspections at a third-party manufacturing site, because of travel restrictions related to the coronavirus disease 2019 pandemic. A new target date has not been announced.

If approved, liso-cel will give patients another option for the treatment of relapsed or refractory (R/R) large B-cell lymphoma, if their disease has progressed after at least two prior therapies. Like its predecessors, liso-cel targets CD19, a surface glycoprotein seen in B-cell development that remains present when the cells become malignant. According to information from Bristol Myers Squibb, the liso-cel CAR mechanism features the following:

an anti-CD19 single-chain variable fragment targeting domain for antigen specificity

a 4-1BB costimulatory domain intended to increase T-cell proliferation and persistence

In addition, liso-cel’s distinct manufacturing process creates a defined composition of CD8+ and CD4+ T-cells, which may reduce product variability; however, the 

, “the clinical significance of defined composition is unknown.”

For insights on what the arrival of liso-cel could mean in the treatment landscape

, director of the Chronic Lymphocytic Leukemia Program at Toni Stephenson Lymphoma Center and associate clinical professor, Department of Hematology & Hematopoietic Cell Transplantation at 

(axi-cel), sold as Yescarta, and the TRANSCEND NHL trial for liso-cel.She has addressed major scientific meetings on the challenge of managing the toxicities associated with CAR T-cell therapy—and discussed how liso-cel represents 

This interview, conducted before the BMS announcement, has been edited for clarity and length.

We're anticipating an FDA decision on liso-cel before the end of the year. Can you discuss the need of the patients who would take this new CAR T-cell therapy?

So, for CAR T-cell therapy targeting CD19-positive B-cell lymphomas—specifically aggressive B-cell lymphomas—we already have a couple of FDA-approved options. The question is: what is liso-cel? How is it different? Why would people pick this over other things? In the trials that we've conducted, we found that liso-cel seems to have lesser toxicity in terms of the specific CAR T-cell side effects of cytokine release syndrome or hyper-inflammation, as well as neurotoxicity. We've just seen fewer severe adverse events so much so that at some [cancer] centers across the country, we’ve been able to give liso-cel CAR T-cells to patients in the clinic or outpatient setting rather than having to admit them to the hospital , depending on the patient's situation.

Those are the strengths of liso-cel—less toxicity and thus, a better chance of giving it in the outpatient setting with hospital admission available to anyone who develops a fever or other side effects. This means fewer days of inpatient hospitalization for these patients, so it may be less costly overall. I don’t think the efficacy is necessarily different—meaning that it seems to work as well as the other FDA-approved products already commercially available. But for the reasons that I've listed, I think it might be a very good option for older patients, maybe patients who are bit more frail, or younger patients who just don't want to be admitted to the hospital—they just want to try to do it in the outpatient setting.

You touched on this already, but can you discuss how Iiso-cel differs from earlier CAR T-cell therapies—both in the way it's manufactured and how it works, and what that reduced variability means for patients?

Liso-celis manufactured in a way that it gives very precise, equal numbers of CAR cells that are labeled CD4 and CD8, in a 1:1 ratio. All of us have T cells to fight infections with, and these T cells are what we take from patients. Then, we modify them in the lab by genetic engineering in order to produce CAR T-cells so that now instead of looking for infections, these CAR T cells are going to look for B-cell lymphoma cells and fight lymphoma.

The other products are given back to patients as a bag of CAR T cells mixed with potentially varying ratios of different types of T cells—CD4+, CD8+, etc. With liso-cel the manufacturing process actually separates out the CD4+ and CD8+ types of T cells first, and then manufactures CAR-T cells out of them separately. So, when we give the cells back to patients, we give it in a 1:1 ratio of CD4+ and CD8+ cells. We know exactly how many CD4+ and how many CD8+ T-cells these patients receive. And the thought is, the researchers and the drug manufacturer feel that this helps to have an expectation of what expansion you will have of these cells in the body. 

Therefore, we potentially have an idea of what type of side effects or how severe the side effects might be. It may limit some of those side effects, or at least make them a little bit more predictable or controlled.

That’s a great way to shift to your own work on length of stay due to CRS. What do we know about the key variables in determining whether a patient will experience a side effect that requires an extended stay in the hospital, and can more be done to avoid lengthy hospital stays?

That's a very important question. Because lengthy hospital stays, especially in the [intensive care unit], really adds to the bill and the financial burden of these treatments. We know that people who have a big burden of disease going into CAR T-cell therapy, meaning they have a lot of lymphoma in their bodies, they tend to be at higher risk for more side effects like cytokine release syndrome and neurotoxicity. Probably because there's so much inflammation that’s generated while these CAR T-cells are trying to fight the lymphoma. What we know is that people who come to us for CAR T-cells with lesser disease might have fewer side effects potentially and a better overall outcome.

So, we always try to advise our referring physicians, and educate patients, at conferences, to try to send these patients to us before they are at the end of the line—before they’ve tried and failed everything, and now there’s just rampant disease. … [At that point,] you're dealing with a situation where the patient is going to have more side effects and will not be able to tolerate the CAR T cells as well. Instead, if they fail two lines of therapy and the disease is still small in volume, but it's starting to progress, we can treat them more effectively with CAR T cells and with fewer side effects potentially.

That brings up the next topic—there have been discussions that CAR T-cell therapy should be given earlier during treatment. As you said, if it’s not given as the last resort, patients might respond better. Where do you see those patterns heading in the future? And would that be truer for some patients than others?

 With aggressive diffuse large B-cell lymphoma, there's about a 60% to 70% chance of curing that in the frontline setting. With the line of chemo-immunotherapy, you can cure 60% to 70% of patients so that it never comes back. But the rest of them—when it just relentlessly keeps coming back and it's hard to cure—once those patients relapse they tend to keep relapsing. So, our mainstay in the relapse setting is to give them salvage chemo-immunotherapy, collect stem cells, and take them to autologous stem cell transplantation if they've achieved a remission with the salvage chemotherapy. If they haven't achieved remission with that salvage chemotherapy, then they should go on to CAR T cells directly instead of waiting and trying more and more chemotherapies. After failing second line therapy, the FDA approval allows us to try CAR T cells. There are studies that are now ongoing that are comparing CAR T cells to autologous stem cell transplantation after failing first line therapy. So, once patients relapse the first time, these studies are comparing giving them salvage chemotherapy and transplant, versus taking them straight to CAR T cells. Once we have that data, we'll know better whether we can do CAR T cells even earlier in the lines of therapy.

We’ve been hearing for some time more about allogeneic or “off-the-shelf” therapies. What progress has been made on in that technology?

I'm not too involved with these trials myself, but I know we have trials at City of Hope that are ongoing with off-the-shelf therapy. What I can tell you is that it's very attractive in that you don't have to collect T cells from patients, keeping their lymphoma under control while these T cells then go to the lab and CAR T cells are manufactured in 2-4 weeks depending on which product it is, and then they come back and get infused. With off-the-shelf products, you can just grab it and go as soon as you know the patient needs it.

The initial concerns were because the cells are not from the patient themselves—the cells are from donors. Across the board there might be concerns of rejection and what's called graft-versus-host disease and things like that. So far, I don't think in the trial they've come up with such side effects to any significant extent. What I don't know is whether they've come up with a good result yet. Is it looking like the benefits of taking off-the-shelf CAR T cells are as good as autologous CAR T cells, meaning patients’ own CAR T cells? I think that remains to be seen. If they are, then it's much easier to use off-the-shelf CAR T cells. Maybe at the American Society of Hematology annual meeting in December we will see more data.

 How is COVID-19 affecting the clinical trial process for CAR T cell therapy?

 When the pandemic kind of started surging early in the year, and when we went into lockdown mode from March onward, we and other centers across the country took a lot of steps to slow down our clinical trial enrollment. Our staff started staggering who would come into work which day of the week and who could work from home. For those in the clinical trials office, there was a lot of need for safety and logistical reasons for us to slow down enrollment onto clinical trials. And there were other questions, such as, who would take care of patients at home once we discharged them after they received CAR T cells? What if their caregivers were exposed and got sick? Logistically, it was difficult to safely do many trials, especially CAR T cell trials and transplants earlier in the year.

Since the end of summer, we ramped up again, and we're now doing as many transplants and CAR T cells as we were probably doing last year. So, we're pretty much all the way up again, but I don't know how this winter will go because COVID is surging again.

As far as just CAR T cells themselves, we had to also think about travel for the cells because Juno Therapeutics is in Seattle, and Kite Pharma is here in Los Angeles, but Novartis is elsewhere. Just the movement of these cells was a concern because of travel restrictions during COVID-19. But as far as I know, the companies did not lose that commitment—they told us, we’ll get the cells to you, we will find a way to do it. I don't think any patients went without cells who should have received cells.

 What advice do you have for community oncologists interested in CAR T cell therapy for their patients?

There’s good news for community physicians. We may soon have a therapeutic option of liso-cel CAR T cell therapy which seems to have lesser side effects. So, this might make things cheaper due to less need for hospitalization potentially without compromising the chance of cure. We want these patients to try CAR T cell therapy sooner rather than later in their relapses. You can always try multiple cycles of chemotherapy at some other time if you relapse again, but if you can be cured with CAR T cells such that you never need treatment again, why not try that first? For the patients who respond well to CAR T cells, the treatment works extremely well. And that's the Holy Grail – to find the cure for all patients.

Maybe only half the patients will currently have a very good and durable response—but those patients may never relapse again. So why not try it sooner rather than later? And of course, we're always looking for trial patients, because now we need to improve these results even further. So, community oncologists should also refer for trials, because I think that it’s very important to have trials with different combinations—CAR T cells plus another immunotherapy agent—to see if we can improve upon the response rates even more.