‘On-your-toes’ approach to managing infection risk needed as CAR T-cell therapy evolves
Chimeric antigen receptor T-cell therapy employs a patient’s immune system to fight cancer and thereby weakens it, leaving the recipient vulnerable to infection.
The overall infection rate for patients who received CAR T cell therapies in pivotal clinical trials ranged from 38% for axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead) to 56% for brexucabtagene autoleucel (Tecartus, Kite Pharma/Gilead). The rate of serious infections (grade 3 or greater) ranged from 19% for lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb) to 33% for tisagenlecleucel (Kymriah, Novartis).
In this installment of In Practice, Joshua A. Hill, MD — assistant professor in the vaccine/infectious disease and clinical research divisions at Fred Hutchinson Cancer Research Center, attending physician within the infectious disease service at Seattle Cancer Care Alliance and assistant professor in the division of allergy and infectious diseases at University of Washington — discusses infection risk during the CAR T-cell therapy process as the technology of CAR T cells continues to evolve, and provides practical advice for clinicians about prevention and mitigation.
Healio: How significant is the risk for infection after CAR T-cell therapy?
Hill: The biggest risk is in the first month after CAR T-cell therapy. Some of this risk is likely due to the side effects of CAR T cells themselves, mainly if the patient develops the inflammatory reaction cytokine release syndrome (CRS) and requires more intensive management in the ICU or with steroids or other targeted therapies. In addition, the chemotherapy patients receive before CAR T-cell therapy adds to immunosuppression.
Approximately 20% to 40% of patients who receive CAR T cells get an infection in the first month. Most of these infections are mild to moderate, with few patients acquiring severe infections. The frequency of infection is comparable with that of patients who receive other types of intensive chemotherapy and, therefore, not necessarily higher than would be expected with other lines of therapy for refractory malignancies.
Healio: Are there any long-term infection risks associated with CAR-T?
Hill: Yes, absolutely. This is a critical question because children are receiving these therapies and achieving longer remissions, so clinicians need to know how to support these patients. As of now, however, there are limited data on long-term risk for infection, and incidence has likely been underreported in retrospective studies.
It’s hard to estimate the true incidence of infection after CAR-T, but we know that it drops off significantly after the first month. On average, the longer-term implications are two to three infections per year, which is probably higher than normal. This is partly because patients can have persistent deficits in their blood cell counts. Another portion is related to previous therapies; a lot of patients who receive CAR T cells have had a previous hematopoietic stem cell transplant, and it takes a long time for the immune system to recover from all these of these treatments, including the CAR T cells.
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. This risk is specific to CAR T-cell therapy because it targets B cells that are part of the underlying malignancy. The CAR T-cell therapies we have today aren’t stealthy enough to kill only the malignant B cells and spare the healthy ones and, therefore, have on-target but off-tumor effects.
B-cell deficits can last a long time: by 1 year out, only 50% to 60% of patients start to recover some of those B cells. We are still learning about the long-term implications of B-cell deficits, including a patient’s ability to have antibody responses to new infections or whether it depletes a patient’s preexisting antibodies. For example, if you were previously vaccinated for chickenpox, you might lose potential antibodies and may need to be re-vaccinated after CAR T-cell therapy. Another question is, could these patients respond to a COVID-19 vaccine? We don’t yet know the answers, but there's a lot of work being done to determine them.
Healio: Does B-cell aplasia contribute to the increased risk for infection after CAR-T?
Hill: No one has been able to quantify how much B-cell depletion specifically contributes to increased risk. To answer this question, we need data from patients who are 6 months or a year out after infusion and still in remission. Then we would need to prospectively follow these patients using a well-designed study. For now, however, this type of data is not available.
Healio: Does infection risk after CAR-T differ depending on the disease type?
Hill: I think it does. Cancer often affects how the immune system functions, and this is especially the case for acute leukemias. Additionally, these patients often receive more intensive therapy regimens and sometimes have undergone HSCT, so it can be hard to disentangle all those different factors.
Nevertheless, I believe the type of disease, and the types of therapies used before CAR T-cell therapy, put certain patients at higher risk for infection. Multiple myeloma is expected to be the next disease approved for CAR T cells, and these therapies specifically target B-cell maturation antigen (BCMA), which is on the surface of plasma cells. We don’t know yet if there will be a difference in infection risk when using CAR T cells that target BCMA instead of CD19. The assumption is that there will be an increased long-term risk for infection with BCMA-targeted CAR T cells because, by targeting the plasma cells, the therapy gives a bigger hit to the immune system by knocking out antibody-producing immune memory cells.
Healio: Does infection risk vary based on the CAR-T product type?
Hill: Different products that have the same target, such as CD19, can vary in construct formulation. This may impact infection risk because one product may persist longer than another. A longer-persisting CAR-T product has more impact on the patient’s immune system that can increase infection risk. It is important to note, however, that this has not been formally indicated through research.
CRS rates differ by CAR-T product type, which may have an effect on infection risk. The newest CAR-T approved by the FDA, lisocabtagene maraleucel, has lower rates of treatment-related and severe CRS. Theoretically, this might reduce the risk for infection.
There are other variations by product to consider, such as the CAR target. This would be CD19 for lymphoma and leukemia vs. BCMA for myeloma. Both targets knock out different parts of the immune system that certainly will have an influence on subsequent infection risk. In my opinion, patients with myeloma who receive BCMA-targeted CAR T cells will have a bigger deficit in their humoral immunity because of the CAR-T cells destroying plasma cells.
Healio: Does infection risk vary based on CAR-T dose level?
Hill: This may be more relevant for clinical trials of CAR-T, especially early-phase trials where different dose levels are studied. The commercial products come in standard doses. However, in a previous study I was part of, we found that a higher dose of CD19-directed CAR T cells in patients with ALL ended up being associated with more frequent CRS, and that ultimately drove up the infection rate.
Healio: Which infection types are common among patients who receive CAR-T?
Hill: Bacterial infections are the most common in the first few weeks to a month after infusion. These infections are partially due to the lymphodepleting chemotherapy patients receive before CAR T-cell infusion, which causes them to become neutropenic and develop the typical bacterial and bloodstream infections due to gram-negative organisms. After that, it is the smattering of infections that we typically see in patients with cancer — a lot of viral infections, mainly in the respiratory tract, in addition to upper respiratory infections and pneumonia.
Healio: What is your methodology for infection prophylaxis for patients who receive CAR-T?
Hill: Last year, I co-authored an article about how to prevent infections in patients receiving CAR T-cell therapy in which we laid out our suggested guidelines. There has not been a good consensus on the topic and society panels have not established best practices in this setting; however, American Society for Transplantation and Cellular Therapy (ASTCT) has put together consensus documents and guidelines.
It is routine practice to give antibacterial prophylaxis during the first week or two after infusion, when patients are neutropenic, and some antifungal prophylaxis. All patients who receive CAR T-cell therapy will be on antibiotics for viral, fungal and bacterial prevention for different durations of time.
The other piece of this is long-term infection prevention. Many patients who receive CAR T-cell therapy receive IV immunoglobulin G therapy on a monthly cycle, but no studies to date have established the effectiveness of this strategy. The benefit of this supplementation is extrapolated from other contexts, especially other types of cancer. IV IgG supplementation is not-well established, is very expensive, can have side effects and is often susceptible to national shortages — particularly in the context of the COVID-19 pandemic. It also is logistically challenging for people to arrange IV IgG supplementation for years after their CAR T-cell infusion. Finally, vaccinations are an important component of the long-term care for these patients, and studies are ongoing to determine how and when to vaccinate patients after they receive CAR T-cell therapy.
Healio: Do you consult any professional guidelines during your decision-making process?
Hill: I would recommend the ASTCT guidelines, although the society does not have a guideline specifically dedicated to infection risks associated with CAR T-cell therapy. ASTCT published guidelines on toxicities related to CAR T-cell therapy for ALL and lymphoma that includes a section pertaining to infection risk and mitigation.
Healio: Is there anything else clinicians should know about infection risk associated with CAR-T?
Hill: Stay on your toes, because these strategies are rapidly changing. There are ongoing trials evaluating this therapy earlier in the disease course and others looking at third-party or “off-the-shelf” CAR T-cell products. Additionally, we are seeing increased use of combination therapy in trials, and I foresee patients receiving other maintenance therapies along with CAR T cells to enhance responses to therapy. The infection risk profile will change as these strategies evolve.
Breyanzi (lisocabtagene maraleucel; prescribing information). Bothell, WA: Bristol Myers Squibb; 2021.
Hill JA, et al. Blood. 2018;doi:10.1182/blood-2017-07-793760.
Hill JA and Seo SK. Blood. 2020;doi:10.1182/blood.2019004000.
Kymriah (tisagenlecleucel; prescribing information). East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2020.
Tecartus (brexucabtagene autoleucel; prescribing information). Santa Monica, CA: Kite Pharma, Inc.; 2021.
Yescarta (axicabtagene ciloleucel; prescribing information). Santa Monica, CA: Kite Pharma, Inc.; 2021.
For more information:
Joshua A. Hill, MD, can be reached at email@example.com.
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