As immune-based therapies for cancer become potent, more effective, and more widely available, optimal management of their unique toxicities becomes increasingly important. Cytokine release syndrome ...(CRS) is a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon γ, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without corticosteroids, can reverse the syndrome. However, because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life-threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of CRS based on severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release ...syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions.
The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale.
We show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Engineered T cell therapies have begun to demonstrate impressive clinical responses in patients with B cell malignancies. Despite this efficacy, many patients are unable to receive T cell therapy ...because of failure of in vitro expansion, a necessary component of cell manufacture and a predictor of in vivo activity. To evaluate the biology underlying these functional differences, we investigated T cell expansion potential and memory phenotype during chemotherapy in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). We found that patients with T cell populations enriched for early lineage cells expanded better in vitro and that patients with ALL had higher numbers of these cells with a corresponding enhancement in expansion as compared to cells from patients with NHL. We further demonstrated that early lineage cells were selectively depleted by cyclophosphamide and cytarabine chemotherapy and that culture with interleukin-7 (IL-7) and IL-15 enriched select early lineage cells and rescued T cell expansion capability. Thus, early lineage cells are essential to T cell fitness for expansion, and enrichment of this population either by timing of T cell collection or culture method can increase the number of patients eligible to receive highly active engineered cellular therapies.
Improved outcomes for patients with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas ...spanning cellular immunology, synthetic biology, and cell-processing technologies has paved the way for clinical applications of chimeric antigen receptor-based therapies. This new form of targeted immunotherapy merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and on elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer.
Translational data on chimeric antigen receptor (CAR) T-cell trials indicate that the presence of naïve T cells in the premanufacture product is important to clinical response and persistence. In ...anticipation of developing CAR trials for other tumors, we investigated the T-cell distribution from children with solid tumors and lymphomas at diagnosis and after every cycle of chemotherapy. We found that patients with T cells enriched for naïve and stem central memory cells expanded well
, but the majority of tumor types showed chemotherapy-related depletion of early lineage cells with a corresponding decline in successful
stimulation response. Unexpectedly, many pediatric patients with solid tumors had low numbers of naïve T cells prior to any therapy. These data indicate the
manufacture of CAR T cells may need to be customized based on the nature of T cells available in each disease type. SIGNIFICANCE: Cumulative chemotherapy cycles deplete naïve T cells in many pediatric cancer regimens, reducing expansion potential associated with successful adoptive cellular therapies. Naïve T-cell deficits can be seen at diagnosis as well, implying immune deficits that exist prior to chemotherapy, which may also affect the development of immune-based therapies.
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Relapsed and refractory acute lymphoblastic leukemia (ALL) remains difficult to treat, with minimal improvement in outcomes seen in more than 2 decades despite advances in upfront therapy and ...improved survival for de novo ALL. Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a powerful targeted immunotherapy, showing striking responses in highly refractory populations. Complete remission (CR) rates as high as 90% have been reported in children and adults with relapsed and refractory ALL treated with CAR-modified T cells targeting the B-cell–specific antigen CD19. Distinct CAR designs across several studies have produced similar promising CR rates, an encouraging finding. Even more encouraging are durable remissions observed in some patients without additional therapy. Duration of remission and CAR-modified T-cell persistence require further study and more mature follow-up, but emerging data suggest these factors may distinguish CAR designs. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome (CRS), posing a unique challenge for toxicity management. This review will discuss the current landscape of CD19 CAR clinical trials, CRS pathophysiology and management, and remaining challenges.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19
relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant ...tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.
Notably, a recent study of simultaneous co-infusion of CD19 and CD22 CAR T cells also demonstrated promising results with high event-free survival rates.4 The success of the study by Pan and ...colleagues lends additional support to the two independent products approach. Keith Chambers/Science Photo Library/Getty Images RMM declares support by 5-K08-CA-277013; and grants from the American Society of Hematology and Alex's Lemonade Stand Foundation. SAG declares research or clinical trial support from Novartis, Servier, Vertex, Cellectis, and Kite; and presence on study steering committees, consulting, or scientific advisory boards for Novartis, Allogene, Adaptimmune, Juno, GSK, CRISPR/Vertex, Jazz, Kyttaro, and Cabaletta.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chimeric antigen receptor (CAR)-modified T cells and bispecific T cell-engaging antibodies have demonstrated dramatic clinical responses in recent clinical trials. The hallmark of these novel highly ...active immunotherapies is nonphysiologic T cell activation, which has correlated not only with greatly increased efficacy but also with notable toxicity in some cases. We and others have observed a cytokine release syndrome (CRS), which correlates with both toxicity and efficacy in patients receiving T cell-engaging therapies. In addition to elevations in effector cytokines, such as interferon-γ, cytokines associated with hemophagocytic lymphohistiocytosis or macrophage activation syndrome, such as interleukin (IL)-10 and IL-6, may also be markedly elevated. Whereas corticosteroids may control some of these toxicities, their potential to block T cell activation and abrogate clinical benefit is a concern. Detailed studies of T cell proliferation and the resultant immune activation produced by these novel therapies have led to more targeted approaches that have the potential to provide superior toxicity control without compromising efficacy. One approach we have developed targets IL-6, a prominent cytokine in CRS, using the IL-6R antagonist tocilizumab. We will review the pathophysiology and management options for CRS associated with T cell-engaging therapies.
Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate ...CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy.
•Tisagenlecleucel (CTL019) has demonstrated clinical efficacy in relapsed/refractory B-cell ALL and CLL.•The cellular kinetic profile of tisagenlecleucel was consistent across the 2 diseases, with higher exposure in responding vs nonresponding patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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