HHS Public Access Author manuscript Author Manuscript
Cancer Discov. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Cancer Discov. 2016 June ; 6(6): 579–580. doi:10.1158/2159-8290.CD-16-0493.
Forecasting Cytokine Storms with New Predictive Biomarkers Rayne H Rouce1,2 and Helen E Heslop1 1Center
for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children’s Hospital, Houston
2Texas
Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston
Author Manuscript
Summary Statement T cells genetically modified with CD19-CARs have produced impressive clinical responses in patients with refractory B cell malignancies but therapeutic responses are often accompanied by cytokine release syndrome, which can cause significant morbidity and mortality. Teachey et al. have identified predictive biomarkers for this complication that may allow testing of earlier intervention with agents such as the IL-6 receptor blocker tocilizumab to evaluate whether CRS can be ameliorated without jeopardizing clinical responses.
Author Manuscript Author Manuscript
Infusion of T cells genetically modified with chimeric antigen receptors (CAR) with specificity against CD19 after lymphodepleting chemotherapy has been one of the major success stories in the field of immuno-oncology. Several groups have reported high remission rates in heavily pre-treated patients with refractory B-cell malignancies;(1–5) however, significant side effects have accompanied these impressive clinical responses. Anti-tumor activity is dependent on T cell activation and proliferation, which results in a systemic inflammatory response known as cytokine release syndrome (CRS). CRS can range from a mild syndrome requiring minimally invasive supportive care to a more severe systemic response necessitating intensive interventions such as vasopressor support and mechanical ventilation.(1–5) In some cases, CRS can present with a constellation of symptoms indistinguishable from hemophagocytic lymphohistiocytosis (HLH) or macrophage activation-like syndrome (MAS). While CRS has rarely been reported after the infusion of T cells that recognize antigens through their native receptor,(6) it has been consistently observed with a frequency of up to 90% in all the successful trials of CD19 CAR-modified T cells despite variation in constructs (single chain variable fragment and costimulatory moieties), vectors, T cell manufacturing methods and lymphodepletion regimens. In addition, a subset of patients treated with CD19 CAR-modified T cells experienced neurologic toxicity that may be concurrent with CRS or may occur as a distinct entity after CRS has resolved.(5)
Corresponding author: Helen E Heslop; ; Email: [email protected]; 1102 Bates Street, Suite 1640, Houston, TX; ph: 832-824-4662, fax:832-825-4732 Contributing author: Rayne H Rouce; [email protected] HEH has a collaborative research agreement with Celgene and Bluebird Bio, a licensing agreement with Cell Medica and is a founder of Viracyte. RHR has no potential conflicts of interest.
Rouce and Heslop
Page 2
Author Manuscript Author Manuscript
As the number of patients treated with CD19-CAR therapy continues to rise, a major research focus has been to identify characteristics and biomarkers that accurately predict whether patients will develop severe CRS. Algorithms have been developed and widely adopted to define severity and guide management (7) but the ability to predict which patients are more likely to develop severe CRS would be valuable, allowing us to test the role of earlier intervention. One consistent risk factor has been disease burden, and most groups are now using lower doses of T cells in patients with more extensive disease. Although the biology of CRS is incompletely understood, measurement of serum cytokines in symptomatic patients has enabled the identification of a group of cytokines deemed responsible for the defining symptoms of CRS. The marked elevation of IL-6 in patients with CRS led to the institution of successful targeted therapy for the treatment of CRS using IL-6 receptor blockade (tocilizumab).(7, 8) Measuring IL-6 however, is a research tool not rapidly available as a CLIA-approved test in most centers. Therefore, the Sloan Kettering group’s observation that levels of C-reactive protein (CRP), for which there is a rapidly available test, correlated with CRS severity was a valuable contribution that since has been widely adopted.(2) Davila and colleagues showed that significant differences in CRP in patients who developed severe CRS were evident as early as 2 days post-infusion and correlated with serum IL-6 levels.(2)
Author Manuscript
In a manuscript published in this issue, Teachey and colleagues from Children’s Hospital of Philadelphia (CHOP) and The University of Pennsylvania sought to address the need for effective predictive biomarkers for CRS by using regression modeling to identify factors predicting patients more likely to develop severe CRS before they become critically ill.(9) They measured the levels of cytokines and other clinical biomarkers in 51 patients, the majority of whom (39) were pediatric and treated with the CD19 CAR CTL019 containing the 41BB costimulatory moiety. 48 of the 51 patients developed CRS, which was Grade 1–2 in 16, Grade 3 in 14 and Grade 4–5 in 14. The authors report peak levels of 24 cytokines (including IFNγ, IL-6, sgp130, and sIL6R) in the first month after infusion, which were highly associated with CRS. In pediatric patients, the modeling analyses were highly accurate and in a forward-selected logistic regression model including IFNγ, IL13, and MIP1 was both highly sensitive at 100% and specific at 96%.(9) They validated this predictive cytokine signature in an independent cohort of 12 pediatric patients, accurately predicting which patients would develop severe CRS. Of note and in contrast to previous reports (2, 5), although peak serum CRP and ferritin were higher in the majority of patients with Grade 4–5 CRS, they failed to predict the development of severe CRS.
Author Manuscript
Despite the success of therapy targeting IL-6 in treating CRS, the authors did not find an appreciable rise in IL-6 prior to development of CRS and concluded that measurement of serum IL-6 early after infusion of CD19-CAR-modified T cells is of no benefit.(9) This observation is in contrast to the findings of Turtle and colleagues from Seattle,(5) who not only found elevated levels of IL-6 (along with IFN-γ, and TNF-α) as early as one day following infusion, but also noted higher IL-6 levels in patients who developed higher grade CRS and also neurotoxicity. The Seattle group also reported that high CAR-T cell doses and larger tumor burden contribute to an increased risk of severe CRS and neurotoxicity,(5)
Cancer Discov. Author manuscript; available in PMC 2017 June 01.
Rouce and Heslop
Page 3
Author Manuscript
which could be mitigated by adoption of a risk-stratified approach where dosing was adjusted based on marrow disease burden. Their stratified approach lowered both ICU admissions for CRS and neurotoxicity.(5)
Author Manuscript
Both the Seattle and Philadelphia reports highlight the importance of developing algorithms that accurately identify patients more likely to develop severe CRS so we may intervene early and test strategies to lower their risk. While the predictive biomarkers identified by Teachey et al were validated in a second pediatric cohort from the CHOP group, it is not yet clear whether the results can be extrapolated to adult patients receiving the same product and to other studies with different CD19 CAR constructs and T cell manufacturing regimens. It seems reasonable to surmise that, just as there are differences in the kinetics of peak expansion and persistence with the different CD19 CAR-modified T cell products currently being tested in the clinic, there may be differences in biomarkers predictive of severe CRS. Indeed, the results from the Seattle group, who are also using a lentiviral construct with the 41BB costimulatory domain, support the contention that factors such as the CAR construct, T cell manufacturing, conditioning regimen and age may influence the biological features of CRS and thus its predictive markers.
Author Manuscript
One important question still to be evaluated is whether earlier intervention with tocilizumab might reduce the morbidity and mortality from CRS without jeopardizing the impressive clinical responses of CD19 CAR-modified T cells. It is unclear whether, if validated, the use of rapid, real-time serum cytokine analysis would be feasible as a clinical decision-making guide in the larger number of centers currently participating in licensing trials of CD19 CAR-modified T cells or whether a clinical manifestation of CRS such as fever reading would be a better guide for intervention. As the authors suggest, prospective trials initiating early intervention based on cytokine profile models or clinical findings will need to be implemented cautiously in order to ensure early intervention strategies do not prematurely abrogate anti-tumor response, especially given the long half-life of tocilizumab.
Acknowledgments Financial Support: Lymphoma Research Foundation 337548 (RHR), American Society of Hematology Harold Amos Foundation (RHR), NCI SPORE P50 CA126752 (HEH), NCI:PPG PO1CA094237 (HEH), NHLBI T32HL092332-06 (HEH), NHLBI U10 HL10894 (HEH), Leukemia and Lymphoma Society SCOR 7018-04 (HEH), CPRIT RP110553-C1 (HEH)
References
Author Manuscript
1. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014; 371(16):1507–17. 10/16/2014. [PubMed: 25317870] 2. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014; 6(224):224ra25. 2/19/2014. 3. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015; 385(9967):517–28. 2/7/2015. [PubMed: 25319501] 4. Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be Cancer Discov. Author manuscript; available in PMC 2017 June 01.
Rouce and Heslop
Page 4
Author Manuscript Author Manuscript
effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015 Feb 20; 33(6):540–9. [PubMed: 25154820] 5. Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016 Apr 25. 6. Papadopoulou A, Krance RA, Allen CE, Lee D, Rooney CM, Brenner MK, et al. Systemic inflammatory response syndrome after administration of unmodified T lymphocytes. Mol Ther. 2014 Jun; 22(6):1134–8. [PubMed: 24651135] 7. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014; 124(2):188–95. 7/10/2014. [PubMed: 24876563] 8. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013; 368(16):1509–18. 4/18/2013. [PubMed: 23527958] 9. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discov. 2016
Author Manuscript Author Manuscript Cancer Discov. Author manuscript; available in PMC 2017 June 01.
Cancer Discov. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Cancer Discov. 2016 June ; 6(6): 579–580. doi:10.1158/2159-8290.CD-16-0493.
Forecasting Cytokine Storms with New Predictive Biomarkers Rayne H Rouce1,2 and Helen E Heslop1 1Center
for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children’s Hospital, Houston
2Texas
Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston
Author Manuscript
Summary Statement T cells genetically modified with CD19-CARs have produced impressive clinical responses in patients with refractory B cell malignancies but therapeutic responses are often accompanied by cytokine release syndrome, which can cause significant morbidity and mortality. Teachey et al. have identified predictive biomarkers for this complication that may allow testing of earlier intervention with agents such as the IL-6 receptor blocker tocilizumab to evaluate whether CRS can be ameliorated without jeopardizing clinical responses.
Author Manuscript Author Manuscript
Infusion of T cells genetically modified with chimeric antigen receptors (CAR) with specificity against CD19 after lymphodepleting chemotherapy has been one of the major success stories in the field of immuno-oncology. Several groups have reported high remission rates in heavily pre-treated patients with refractory B-cell malignancies;(1–5) however, significant side effects have accompanied these impressive clinical responses. Anti-tumor activity is dependent on T cell activation and proliferation, which results in a systemic inflammatory response known as cytokine release syndrome (CRS). CRS can range from a mild syndrome requiring minimally invasive supportive care to a more severe systemic response necessitating intensive interventions such as vasopressor support and mechanical ventilation.(1–5) In some cases, CRS can present with a constellation of symptoms indistinguishable from hemophagocytic lymphohistiocytosis (HLH) or macrophage activation-like syndrome (MAS). While CRS has rarely been reported after the infusion of T cells that recognize antigens through their native receptor,(6) it has been consistently observed with a frequency of up to 90% in all the successful trials of CD19 CAR-modified T cells despite variation in constructs (single chain variable fragment and costimulatory moieties), vectors, T cell manufacturing methods and lymphodepletion regimens. In addition, a subset of patients treated with CD19 CAR-modified T cells experienced neurologic toxicity that may be concurrent with CRS or may occur as a distinct entity after CRS has resolved.(5)
Corresponding author: Helen E Heslop; ; Email: [email protected]; 1102 Bates Street, Suite 1640, Houston, TX; ph: 832-824-4662, fax:832-825-4732 Contributing author: Rayne H Rouce; [email protected] HEH has a collaborative research agreement with Celgene and Bluebird Bio, a licensing agreement with Cell Medica and is a founder of Viracyte. RHR has no potential conflicts of interest.
Rouce and Heslop
Page 2
Author Manuscript Author Manuscript
As the number of patients treated with CD19-CAR therapy continues to rise, a major research focus has been to identify characteristics and biomarkers that accurately predict whether patients will develop severe CRS. Algorithms have been developed and widely adopted to define severity and guide management (7) but the ability to predict which patients are more likely to develop severe CRS would be valuable, allowing us to test the role of earlier intervention. One consistent risk factor has been disease burden, and most groups are now using lower doses of T cells in patients with more extensive disease. Although the biology of CRS is incompletely understood, measurement of serum cytokines in symptomatic patients has enabled the identification of a group of cytokines deemed responsible for the defining symptoms of CRS. The marked elevation of IL-6 in patients with CRS led to the institution of successful targeted therapy for the treatment of CRS using IL-6 receptor blockade (tocilizumab).(7, 8) Measuring IL-6 however, is a research tool not rapidly available as a CLIA-approved test in most centers. Therefore, the Sloan Kettering group’s observation that levels of C-reactive protein (CRP), for which there is a rapidly available test, correlated with CRS severity was a valuable contribution that since has been widely adopted.(2) Davila and colleagues showed that significant differences in CRP in patients who developed severe CRS were evident as early as 2 days post-infusion and correlated with serum IL-6 levels.(2)
Author Manuscript
In a manuscript published in this issue, Teachey and colleagues from Children’s Hospital of Philadelphia (CHOP) and The University of Pennsylvania sought to address the need for effective predictive biomarkers for CRS by using regression modeling to identify factors predicting patients more likely to develop severe CRS before they become critically ill.(9) They measured the levels of cytokines and other clinical biomarkers in 51 patients, the majority of whom (39) were pediatric and treated with the CD19 CAR CTL019 containing the 41BB costimulatory moiety. 48 of the 51 patients developed CRS, which was Grade 1–2 in 16, Grade 3 in 14 and Grade 4–5 in 14. The authors report peak levels of 24 cytokines (including IFNγ, IL-6, sgp130, and sIL6R) in the first month after infusion, which were highly associated with CRS. In pediatric patients, the modeling analyses were highly accurate and in a forward-selected logistic regression model including IFNγ, IL13, and MIP1 was both highly sensitive at 100% and specific at 96%.(9) They validated this predictive cytokine signature in an independent cohort of 12 pediatric patients, accurately predicting which patients would develop severe CRS. Of note and in contrast to previous reports (2, 5), although peak serum CRP and ferritin were higher in the majority of patients with Grade 4–5 CRS, they failed to predict the development of severe CRS.
Author Manuscript
Despite the success of therapy targeting IL-6 in treating CRS, the authors did not find an appreciable rise in IL-6 prior to development of CRS and concluded that measurement of serum IL-6 early after infusion of CD19-CAR-modified T cells is of no benefit.(9) This observation is in contrast to the findings of Turtle and colleagues from Seattle,(5) who not only found elevated levels of IL-6 (along with IFN-γ, and TNF-α) as early as one day following infusion, but also noted higher IL-6 levels in patients who developed higher grade CRS and also neurotoxicity. The Seattle group also reported that high CAR-T cell doses and larger tumor burden contribute to an increased risk of severe CRS and neurotoxicity,(5)
Cancer Discov. Author manuscript; available in PMC 2017 June 01.
Rouce and Heslop
Page 3
Author Manuscript
which could be mitigated by adoption of a risk-stratified approach where dosing was adjusted based on marrow disease burden. Their stratified approach lowered both ICU admissions for CRS and neurotoxicity.(5)
Author Manuscript
Both the Seattle and Philadelphia reports highlight the importance of developing algorithms that accurately identify patients more likely to develop severe CRS so we may intervene early and test strategies to lower their risk. While the predictive biomarkers identified by Teachey et al were validated in a second pediatric cohort from the CHOP group, it is not yet clear whether the results can be extrapolated to adult patients receiving the same product and to other studies with different CD19 CAR constructs and T cell manufacturing regimens. It seems reasonable to surmise that, just as there are differences in the kinetics of peak expansion and persistence with the different CD19 CAR-modified T cell products currently being tested in the clinic, there may be differences in biomarkers predictive of severe CRS. Indeed, the results from the Seattle group, who are also using a lentiviral construct with the 41BB costimulatory domain, support the contention that factors such as the CAR construct, T cell manufacturing, conditioning regimen and age may influence the biological features of CRS and thus its predictive markers.
Author Manuscript
One important question still to be evaluated is whether earlier intervention with tocilizumab might reduce the morbidity and mortality from CRS without jeopardizing the impressive clinical responses of CD19 CAR-modified T cells. It is unclear whether, if validated, the use of rapid, real-time serum cytokine analysis would be feasible as a clinical decision-making guide in the larger number of centers currently participating in licensing trials of CD19 CAR-modified T cells or whether a clinical manifestation of CRS such as fever reading would be a better guide for intervention. As the authors suggest, prospective trials initiating early intervention based on cytokine profile models or clinical findings will need to be implemented cautiously in order to ensure early intervention strategies do not prematurely abrogate anti-tumor response, especially given the long half-life of tocilizumab.
Acknowledgments Financial Support: Lymphoma Research Foundation 337548 (RHR), American Society of Hematology Harold Amos Foundation (RHR), NCI SPORE P50 CA126752 (HEH), NCI:PPG PO1CA094237 (HEH), NHLBI T32HL092332-06 (HEH), NHLBI U10 HL10894 (HEH), Leukemia and Lymphoma Society SCOR 7018-04 (HEH), CPRIT RP110553-C1 (HEH)
References
Author Manuscript
1. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014; 371(16):1507–17. 10/16/2014. [PubMed: 25317870] 2. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014; 6(224):224ra25. 2/19/2014. 3. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015; 385(9967):517–28. 2/7/2015. [PubMed: 25319501] 4. Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be Cancer Discov. Author manuscript; available in PMC 2017 June 01.
Rouce and Heslop
Page 4
Author Manuscript Author Manuscript
effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015 Feb 20; 33(6):540–9. [PubMed: 25154820] 5. Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016 Apr 25. 6. Papadopoulou A, Krance RA, Allen CE, Lee D, Rooney CM, Brenner MK, et al. Systemic inflammatory response syndrome after administration of unmodified T lymphocytes. Mol Ther. 2014 Jun; 22(6):1134–8. [PubMed: 24651135] 7. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014; 124(2):188–95. 7/10/2014. [PubMed: 24876563] 8. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013; 368(16):1509–18. 4/18/2013. [PubMed: 23527958] 9. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discov. 2016
Author Manuscript Author Manuscript Cancer Discov. Author manuscript; available in PMC 2017 June 01.
