Navigating the narrow bridge to CAR T-cell therapy (2023)


When the pivotal phase 2 ZUMA-1 trial was first published in the New England Journal of Medicine in 2017, chimeric antigen receptor (CAR) T-cell therapy was widely regarded as a major breakthrough for patients with refractory diffuse large B-cell lymphoma. These patients, who historically would have had dismal outcomes, had an objective response rate of 82% and an 18-month overall survival of 52%.1 The results of ZUMA-1 were subsequently bolstered by the JULIET study, in which patients had an equally impressive 12-month relapse-free survival of 65%.2 Of course, the patients on the ZUMA-1 and JULIET trials were carefully selected, as is the case in most clinical trials, and likely consisted of a less-sick cohort. In particular, the ZUMA-1 trial notably did not allow for any bridging therapy. In reality, patients who are candidates for CAR T-cell therapy often have progressive symptomatic disease that requires some form of treatment to support them during the period between leukapheresis and CAR T-cell infusion.

In this issue, Pinnix et al compare the outcomes of 81 patients who received any bridging therapy prior to planned treatment with commercially available axicabtagene ciloleucel to 67 patients who did not.3 Notably, the patients who received bridging therapy had worse 1-year progression-free survival (PFS) and overall survival than patients who did not. Bridging itself is unlikely to have led to worse outcomes; instead, the patients who needed bridging therapy were likely sicker than those who did not. It is also important to note that the entire cohort had worse outcomes than those published in the ZUMA-1 and JULIET trials, likely representing an ambitious attempt to give CAR T-cell therapy to all eligible patients, a de facto “real-world” experience. One in 6 patients in this series did not go on to receive the planned CAR T-cell therapy, most commonly because of disease progression and despite best efforts with bridging therapy. These data suggest that earlier referrals for consideration of CAR T-cell therapy, before the patient is in a dire condition, may be important.

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At present, there are more unknowns than knowns about how to best bridge patients to CAR T-cell therapy and about the effect of bridging therapy on outcomes, including toxicity. These are highlighted eloquently in the hypothesis-generating paper by Pinnix et al, which included patients bridged with systemic therapy, radiation therapy (RT), and combined modality therapy. Most importantly, there is the question of how to best bridge these patients. In this paper, there was a suggestion that patients bridged with RT had improved PFS as compared with patients bridged with systemic therapy. Because 69% of patients bridged with systemic therapy received cytotoxic chemotherapy, perhaps this is an indication that this may not be the optimal strategy for patients with chemorefractory disease. All patients in this series who had bridging with RT went on to receive CAR T cells as compared with only 74% of patients who had bridging with systemic therapy. Also of note, patients bridged with RT also had higher response rates than patients bridged with systemic therapy alone, though it is possible that patients selected for RT bridging had more limited disease. This may also partially explain why patients who received RT bridging had better outcomes than patients who received other types of bridging and had a 1-year PFS that was comparable to those select patients who did not require bridging therapy.

For patients who undergo bridging with RT, a second set of questions must be answered regarding the timing, the dose and fractionation, and the field size. At present, the most common practice is for the patient to undergo leukapheresis, followed by RT prior to infusion of the CAR T-cell product. Interestingly, in the MD Anderson series, 2 patients had leukapheresis after the start of RT but still went on to have successful manufacturing and infusion of the CAR T-cell product. The median time from leukapheresis to axicabtagene ciloleucel infusion was 29 days for all patients with no difference between the bridged and nonbridged patients; this was most certainly due to excellent coordination of care, which may not be as readily available at institutions with less CAR T-cell therapy experience.

The second question specific to RT bridging pertains to the optimal dose. Previously published series have used a variety of fractionation schemes including 3 Gy × 10 fractions and 4 Gy × 5 fractions with good tolerance and effect.4 The benefit of a shorter course is that it facilitates fast treatment in the window between leukapheresis and CAR T-cell infusion. The disadvantage is that these doses may not be optimal to definitively treat aggressive non-Hodgkin lymphomas. This may be particularly relevant for patients who do not get any benefit from CAR T cells, whether from failed manufacturing or lack of antitumor effect. With adequate care coordination, some patients with more limited disease may benefit from comprehensive treatment using smaller fractions to standard doses of 36 to 40 Gy, as was done for many of the patients in the Pinnix et al series.

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The last question specific to RT bridging is how much disease should be treated? Should all of the disease be irradiated using a comprehensive RT field, as was done for 9 patients in this cohort, or should a focal RT field that excludes active disease be used instead? In the Pinnix et al series, 75% of patients treated focally progressed or relapsed, with the majority of these relapses in sites of active lymphoma excluded from the RT field. Although it conceptually makes sense to attempt to debulk disease as much as possible prior to CAR T-cell infusion, there are some potential pitfalls. Practically, the larger the field, the more concern there is for toxicity. Theoretically, there is the potential risk that without adequate antigen, patients may have inadequate T-cell activation, although the patients who were treated comprehensively in this cohort still did well. Additional research is needed to better evaluate how expansion is impacted when patients achieve a complete response prior to CAR T-cell therapy.5

Finally, there is the question of whether bridging therapy can decrease toxicity, specifically grade 3 or higher cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. These toxicities are difficult and expensive to manage as well as potentially fatal. There were no deaths in the group receiving RT bridging although there were 7 deaths in the group receiving systemic therapy bridging, most commonly from septic shock. Notably, all of the patients who died of infectious complications had received cytotoxic chemotherapy bridging, an important observation in this group of heavily pretreated patients. Data are emerging from the University of Pennsylvania that tumor burden may affect the incidence of cytokine release syndrome, thus suggesting that adequate debulking with bridging therapy prior to CAR T-cell infusion may help to decrease acute toxicity.6

Although these initial data from Pinnix et al suggest a role for bridging therapy, and specifically bridging RT, prior to CAR T-cell therapy, the unknowns remain. The International Lymphoma Radiation Oncology Group (ILROG) has created an RT/CAR T-cell Consortium to study the questions highlighted by this series in a coordinated and collaborative way. Until more data are available, the most salient lesson learned appears to be that CAR T-cell candidates benefit from an early referral for care coordination, particularly if bridging therapy is being considered. A silver lining in the era of the COVID-19 pandemic is the strengthening of virtual tumor boards and telemedicine capabilities. With reduced barriers to multidisciplinary care and tertiary referrals to expert centers, CAR T-cell therapy will hopefully be optimized for each patient, whether via appropriate bridging or the decision to pursue CAR T-cell therapy at all.

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1. Neelapu SS, Locke FL, Bartlett NL, et al.. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. [PMC free article] [PubMed] [Google Scholar]

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2. Schuster SJ, Svoboda J, Chong EA, et al.. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545-2554. [PMC free article] [PubMed] [Google Scholar]

3. Pinnix CC, Gunther JR, Dabaja BS, et al. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma. Blood Adv2020;4(13):2871-2883. [PMC free article] [PubMed] [Google Scholar]

4. Sim AJ, Jain MD, Figura NB, et al.. Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene ciloleucel in diffuse large B-cell lymphoma. Int J Radiat Oncol Biol Phys. 2019;105(5):1012-1021. [PMC free article] [PubMed] [Google Scholar]

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5. Bishop MR, Maziarz RT, Waller EK, et al.. Tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma patients without measurable disease at infusion. Blood Adv. 2019;3(14):2230-2236. [PMC free article] [PubMed] [Google Scholar]

6. Wright CM, LaRiviere MJ, Baron JA, et al.. Bridging radiation therapy prior to commercial chimeric antigen receptor T-cell therapy for relapsed/refractory non-Hodgkin lymphoma [published online ahead of print 21 May 2020]. Int J Radiat Oncol Biol Phys. Available from: 10.1016/j.ijrobp.2020.05.014. [PubMed] [CrossRef] [Google Scholar]


What is bridging therapy for CAR T cells? ›

In the context of CAR T-cell therapy, bridging therapy refers to treatments between apheresis and lymphodepleting chemotherapy. These treatments aim to slow disease progression during this critical interval period, prior to CAR T-cell infusion.

What is the most logical approach to improve CAR T-cell therapy? ›

Combinational antigen recognition is the most logical way to improve the safety of cancer therapy.

What is the survival rate of CAR T-cell therapy? ›

Clinical studies have proven that up to 92 % of treated patients suffering from Acute Lymphatic Leukemia (ALL) could be fully cured.

What is the disadvantage of CAR T-cell therapy? ›

A major hurdle to CAR-T cell therapy is severe toxicities. The most common toxicities following infusion of CAR-T cells are CRS, neurologic toxicity, tumor lysis syndrome (TLS), on-target-off-tumor effects, anaphylaxis, and hematologic toxicities (19, 86, 87) ( Figure 4 ).

How do you feel after CAR T-cell therapy? ›

Patients may experience fever, weakness, chills and loss of appetite. These side effects typically start a few days after the CAR T cell transfusion and last about a week. CAR T cell-related encephalopathy syndrome side effects are less common but more severe because they involve the brain.

How does bridging therapy work? ›

"Bridging” is a term that refers to the use of short-acting anticoagulants (heparin or LMWH) for a period of time during the interruption of warfarin therapy when the INR is not within a therapeutic range. There is no established single bridging regimen.

How do I prepare for CAR T-cell therapy? ›

In preparation for your CAR-T cell infusion, you will undergo chemotherapy. Most people start chemotherapy about five days before CAR-T cell infusion. At this time, day-to-day care likely changes to a hospital-based care team. Your care team monitors your health and progress each day.

Which cancers respond well to CAR T therapy? ›

Chimeric antigen receptor (CAR) T cell therapy has been an amazing advance for treating blood cancers like leukemia, lymphoma and multiple myeloma. Now, it is showing promise for solid tumors — from lung cancer to kidney cancer to bone cancer — as well.

What is the ideal target for CAR T-cell therapy? ›

The CAR T-cell therapies approved by FDA to date target one of two antigens on B cells, CD19 or BCMA.

How many times can you have CAR T-cell therapy? ›

For most people, CAR T is a one-time treatment and the T cells remain in the body for months and years. For some, the T cells go away quickly. In patients who have lost the cells quickly, the treatment can be repeated safely.

Do you lose your hair with CAR T-cell therapy? ›

Will I lose my hair during CAR T-cell therapy? Patients who undergo CAR T-cell therapy typically do not lose their hair or experience some of the other common side effects of chemotherapy, such as nausea and vomiting.

Is CAR T-cell therapy a last resort? ›

CAR T-cell therapy is sometimes understood as a last resort treatment option for patients with specific types of cancer that have not found success with other treatments. The reason is that CAR T-cell therapy is a new treatment only approved for use for only a few cancers, including leukemia and lymphoma.

What are the long-term side effects of CAR T-cell? ›

The most prominent long-term toxicities after CAR T cell therapy include cytopenias and hypogammaglobulinaemia. The incidence of severe infections >1 month after CAR T cell therapy is low compared to infections seen in the acute period immediately after cell infusion.

What are the neurological complications of CAR T-cell therapy? ›

Neurological toxicity associated with CAR T-cell therapy, known as immune effector cell-associated neurotoxicity syndrome (ICANS), affects approximately 50 percent of recipients. Symptoms include confusion, delirium, aphasia, impaired motor skills, and somnolence.

Who is not eligible for CAR T-cell therapy? ›

A patient who is wheelchair bound and who can't tolerate chemotherapy is likely not a good candidate for CAR T,” Locke said. “But a patient in their 70s with hypertension and diabetes may still be eligible. It's important to not rule them out and to consider all factors.”

Does insurance pay for CAR T-cell therapy? ›

Many private health insurance plans cover CAR T-cell therapy, but other plans don't. Some pay limited amounts only. Medicare covers CAR T-cell therapy. Medicaid covers it as well, but only in certain states.

How long does fatigue last after CAR T-cell therapy? ›

Like many cancer treatments, CAR T-cell therapy is associated with fatigue: one trial reported that 51% of patients experienced the symptom, although it usually resolved within four to six weeks after infusion.

Is CAR-T better than chemo? ›

Pinpointing Your Immune System Against Cancer

CAR T-cell therapy may work when other treatments haven't. And unlike chemo and radiation, which kill healthy cells as well as cancerous ones, immunotherapy targets the tumors with more precision. CAR T-cell therapy, or CAR T, is one of a few types of immunotherapy.

When should I start bridging therapy? ›

How Is Bridging Anticoagulation Given? After warfarin is stopped, 5 to 6 days before surgery (to allow sufficient time for its anticoagulant effect to wane), bridging anticoagulation is started 3 days before surgery, with the last dose given 24 hours before surgery.

When is bridging therapy necessary? ›

Guidelines suggest that patients at high risk of thromboembolism receive bridging anticoagulation. This group includes patients with a CHADS2 score of 5 or 6, most patients with mechanical heart valves, and those with recent ischemic stroke or TIA, or recent deep vein thrombosis or pulmonary embolism (Box 2).

How long is bridging therapy? ›

In this analysis, the duration of bridging therapy ranged from 2 days to 129 days, and a variety of regimens were used. Of these patients, five remained progression-free for more than 12 months, and this group of patients was found to have low rates of cytokine release syndrome (CRS) and neurotoxicity.

How long does it take to recover from CAR T-cell therapy? ›

Recovery: Patients who receive CAR T-cell therapy have a risk/recovery period of approximately 2-3 months. During this period, patients will be evaluated for side effects and treatment response.

What are the stages of CAR T therapy? ›

Stages of CAR T therapy

collecting the T cells. treating the T cells in the laboratory. conditioning chemotherapy, which prepares your immune system to receive the CAR T cells. infusion, where the reprogrammed cells are infused back into you.

How long does CAR T-cell infusion take? ›

Infusing the CAR T cells: This usually takes no more than an hour, though it could be as quick as 15 minutes. It depends on how many bags of cells are being infused, and if you have a reaction.

Who is a candidate for CAR-T therapy? ›

What type of patient is a good candidate for CAR T-cell therapy? Currently, a pediatric acute lymphoblastic leukemia or an adult aggressive B-cell lymphoma patient who has already been through two lines of unsuccessful treatment is ideal to receive CAR T-cell therapy.

What is the total cost of CAR T-cell therapy? ›

The mean pharmacy cost for patients who received CAR T-cell therapy was $330,070 vs $44,770 and $57,701 for autologous and allogeneic SCT, respectively.

What are the three approved CAR T-cell therapy drugs? ›

Cancers with FDA-approved CAR T-cell therapies

Kymriah (tisagenlecleucel) Tecartus (brexucabtagene autoleucel) Yescarta (axicabtagene ciloleucel) Carvykti (ciltacabtagene autoleucel)

Why is CAR T-cell therapy so good? ›

CAR T-cell therapy is also a “living drug”, and its benefits can last for many years. Since the cells can persist in the body long-term, they may recognize and attack cancer cells if and when there's a relapse.

How long are you immunocompromised after CAR T? ›

Many patients do not recover their T cells and B cells for 6 months to a year, so they have prolonged immune deficits that can last beyond 6 months.

How safe is CAR-T therapy? ›

Although CAR T-cell therapy is a relatively safe therapeutic option in patients with glioblastoma, it shows marginal efficacy, suggesting that further research is necessary for its translation into clinical practice for the treatment of recurrent glioblastoma.

Does CAR T-cell therapy have cardiac side effects? ›

Conclusion: Cancer patients treated with CAR-T cell therapy were at risk for cardiovascular toxicities, of which the most common cardiovascular events were arrhythmias, cardiovascular dysfunction, and heart failure.

What are the symptoms of CAR-T neurotoxicity? ›

Chimeric antigen receptor-T cell-associated neurotoxicity comprises a wide range of signs and symptoms, including delirium, headache, language disturbance, tremor, transient focal weakness, behavioral disturbances, ataxia, peripheral neuropathy, visual changes and generalized weakness, seizures, and acute cerebral ...

Who pays for CAR-T therapy? ›

Medicare currently pays for therapies like CAR-T at the average sales price plus a margin of 4.3% to cover costs associated with delivering these therapies.

How do you know if CAR T-cell therapy is working? ›

After about 3 months, the doctor will check to see if the CAR T cells worked. It's important to note that CAR T cells kill all cells against which they are directed, including normal cells. This usually results in a weak immune system for several months following treatment.

Is CAR T-cell therapy worth it? ›

CAR T cell therapy can be a lifesaving treatment

Although there is still work to be done, the treatment has been lifesaving for many. A significant number of patients treated with CAR T cells will be long-term survivors. That's phenomenal, considering many were given a slim to none chance of survival.

What cancers respond to CAR T-cell therapy? ›

CAR T cell therapy is used to treat certain kinds of lymphoma, pediatric leukemia, and adult leukemia. It is also being investigated for the treatment of other cancers, including some solid tumors that appear in the chest.

What are the long term side effects of CAR T-cell therapy? ›

The most prominent long-term toxicities after CAR T cell therapy include cytopenias and hypogammaglobulinaemia. The incidence of severe infections >1 month after CAR T cell therapy is low compared to infections seen in the acute period immediately after cell infusion.

Who is a good candidate for CAR T-cell therapy? ›

What type of patient is a good candidate for CAR T-cell therapy? Currently, a pediatric acute lymphoblastic leukemia or an adult aggressive B-cell lymphoma patient who has already been through two lines of unsuccessful treatment is ideal to receive CAR T-cell therapy.

Will I lose my hair with CAR T-cell therapy? ›

Will I lose my hair during CAR T-cell therapy? Patients who undergo CAR T-cell therapy typically do not lose their hair or experience some of the other common side effects of chemotherapy, such as nausea and vomiting.

What is the average cost of CAR-T therapy? ›

How Much Is CAR T-Cell Therapy? Experts estimate that CAR T-cell therapy can cost between $500,000 and $1,000,000. “CAR [T-cell therapy] is the most expensive Medicare diagnosis-related drug,” says Brian Koffman, MD, founder of the Chronic Lymphocytic Leukemia Society.

How much does CAR T-cell therapy cost in the US? ›

The cost of treating CRS ranges from $30,000 to $56,000 per patient [28]. The total treatment cost for CAR T-cell therapy has been estimated to reach up to $500,000 for patients with severe CRS [28].

What is the timeline for CAR T treatment? ›

The entire CAR T cell therapy process takes about three months to complete, from the time your doctor orders an eligibility assessment until you finish the 30-day observation period after the infusion.

What are two potential side effects of CAR T-cell therapy? ›

Like most cancer treatments, CAR T-cell therapy has side effects that can, at times, cause serious life-threatening problems. The two most common side effects are cytokine release syndrome and neurological problems.

Why does CAR T-cell therapy fail? ›

There are several reasons why CAR T-cell therapy may fail: The cancer cells may stop making the antigen targeted by the therapy, which means the T-cells that were engineered for that specific antigen won't work. This is called antigen loss.

Is CAR T better than chemo? ›

Pinpointing Your Immune System Against Cancer

CAR T-cell therapy may work when other treatments haven't. And unlike chemo and radiation, which kill healthy cells as well as cancerous ones, immunotherapy targets the tumors with more precision. CAR T-cell therapy, or CAR T, is one of a few types of immunotherapy.


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