Cardiotoxicity of T-Cell Antineoplastic Therapies: JACC: CardioOncology Primer.

T-cell therapies, such as chimeric antigen receptor (CAR) T-cell, bispecific T-cell engager (BiTE), and tumor-infiltrating lymphocyte (TIL) therapies, have changed the treatment landscape for patients with a variety of malignancies. 1 , 2 , 3 However, these therapies can be associated with adverse cardiovascular effects. Although clinical trials included patients without significant cardiovascular comorbidities, real-world use of these therapies includes patients with pre-existing cardiovascular risk factors and disease, increasing the potential for associated cardiotoxicities. Hence, awareness and surveillance are crucial for early recognition and treatment of cardiotoxicity.

CAR T cells are patient-derived T cells that are genetically engineered to target a tumor-specific antigen, such as CD19 or BCMA (B-cell maturation antigen), to induce tumor-cell apoptosis. 1 BiTE molecules are fusion proteins with 2 different antigen-binding sites: one directed against the CD3 receptor, which leads to downstream activation of cytotoxic T lymphocytes, and another directed specifically at an antigen present on malignant cells. 2 , 4 TILs are isolated from the tumor site, stimulated with interleukin (IL)-2, grown in vitro, and then infused back into the patient. 3 Although the target antigens are preidentified and T-cell therapies are manufactured to fight cancer cells harboring those antigens, activation of the immune response can cascade and lead to systemic inflammation and downstream adverse effects, including cardiotoxicity ( Figure 1 ).

Mechanisms and Manifestations of Cardiotoxicity

The mechanisms underlying immune-mediated cardiotoxicity can be divided into 3 broad categories: 1) on-target, on-tumor effects that lead to cytokine release syndrome (CRS); 2) on-target, off-tumor effects: direct T-cell-mediated injury of recipient organs that share target antigens with the tumor; and 3) off-target, off-tumor effects: the T cells unexpectedly attack an antigen other than the intended tumor antigen ( Figure 1 ). 2 , 3 , 4

Information regarding T-cell therapy–associated cardiotoxicity is based primarily on experience with CAR T-cell therapy. Evidence thus far suggests that cardiotoxicity occurs mainly in the context of CRS and is correlated with CRS severity. However, it is unclear if cardiotoxicity is merely an epiphenomenon of CRS. Additionally, certain CAR T-cell constructs, such as those directed against melanoma-associated antigen-3, demonstrated cross-reactivity against titin, a striated muscle protein in the heart, to cause fatal, fulminant myocarditis. 5 Furthermore, lymphodepletion with potentially cardiotoxic agents such as cyclophosphamide and anthracyclines, given prior to some T-cell therapies, may also contribute to the development of adverse cardiovascular events.

Activation of the immune system by T-cell therapies leads to a surge in circulating cytokines and chemokines (such as IL-2, interferon-alpha, IL-6, and granulocyte-macrophage colony-stimulating factor) that originate from the infused cells themselves, from activation and recruitment of other local immune cells (such as monocytes, macrophages, and dendritic cells), and as a result of therapy-mediated tumor-cell lysis. 6 This surge in cytokines can lead to a systemic inflammatory response, called CRS, which is characterized by fever and one or more of the following presentations: hypotension, hypoxia, and organ toxicity. Although many grading systems exist, the system put forth by the American Society for Transplantation and Cellular Therapy is commonly used to grade the severity of CRS. 7 CRS has been reported in 70% to 90% of patients undergoing CAR T-cell therapy. Although CRS is mostly mild in severity (grade 1), some patients exhibit serious systemic adverse effects (grades 2-4), including cardiovascular complications such as cardiomyopathy, heart failure (HF), arrhythmias, myocardial infarction and vascular leak syndrome with associated circulatory collapse and multiorgan failure. 8 , 9 , 10

Among the cytokines involved in the inflammatory cascade, IL-6 has been implicated as a key mediator of CRS and in the pathophysiology of T-cell therapy–associated cardiotoxicity. 9 IL-6 up-regulation activates the gp130/STAT3 signaling pathway to promote oxidative stress, leading to mitochondrial dysfunction and cardiac hypertrophy. The increase in reactive oxygen species also increases cardiomyocyte apoptosis. In addition, IL-6 alters Ca 2+ handling and reduces myocardial contractility, potentially resulting in diastolic dysfunction and arrhythmias. 11

Incidence of Cardiotoxicity

CAR T-cell therapy

Clinical trials of CAR T-cell therapy have reported low rates of cardiotoxicity, possibly due to selective patient enrollment. However, subsequent retrospective cohort studies have noted major adverse cardiovascular events (MACE) in 10% to 20% of patients ( Table 1 ).

A retrospective study of 145 patients receiving CAR T-cell therapy for a variety of hematologic malignancies, with median follow-up of 456 days, reported 15% incidence of HF, 7.5% incidence of atrial fibrillation with 2 events of other arrhythmias (supraventricular tachycardia and nonsustained ventricular tachycardia), 2 episodes of acute coronary syndrome, 2 cardiac deaths attributed to pulseless electric activity, and a massive pulmonary embolism leading to ST-segment elevation myocardial infarction. 12

An analysis of CAR T-cell therapy–related individual case safety reports (ICSRs) submitted to VigiBase, the international World Health Organization pharmacovigilance database, noted that 13% of ICSRs were related to cardiotoxicity, including cardiac arrhythmias, pericardial effusion, stress cardiomyopathy, left ventricular dysfunction, and cardiac arrest. Notably, 25% of these cases were fatal. Interestingly, cardiotoxicity-related ICSRs were more frequent with axicabtagene-ciloleucel (57.3%) compared with tisagenlecleucel-T (42.7%). 13

Various arrhythmias have been reported with CAR T-cell therapy, with an incidence ranging from 5% to 12%. In another pharmacovigilance study leveraging the U.S. Food and Drug Administration Adverse Events Reporting System, the reporting OR was highest for atrial fibrillation, followed by ventricular arrhythmias. In age- and sex-adjusted models, tachyarrhythmias were reported more frequently with axicabtagene-ciloleucel than tisagenlecleucel. 14

In a retrospective multi-institutional study of 116 patients undergoing CD19-targeted CAR T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma, 10% developed new or worsening cardiomyopathy, with a median decline in left ventricular ejection fraction (LVEF) from 58% to 37% on serial echocardiography performed in the context of high-grade CRS. 10 Although similar rates of cardiomyopathy were seen in a pediatric study of patients treated with CAR T-cell therapy for acute lymphoblastic leukemia, 15 another study of 137 adult patients with CAR T-cell therapy for lymphomas and multiple myeloma reported cardiomyopathy in 5.8% patients, which may be an underestimate given the lack of systematic echocardiographic surveillance in this study. 8

Evidence regarding the risk for CRS and cardiotoxicity is based largely on CD19-directed CAR T-cell therapy. Available data from one clinical trial suggest that the occurrence of all-grade and high-grade CRS is similar with BCMA-directed CAR T-cell therapy. 16

BiTE and TIL

Data regarding the incidence of cardiotoxicity with BiTE and TIL therapies are limited ( Table 1 ). In the phase 3 TOWER (Blinatumomab Versus Standard of Care Chemotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia) trial of blinatumomab (BiTE therapy), CRS was reported in 14.2% of patients, with grade ≥3 CRS in about 5% of patients. 2 A subsequent real-world study of blinatumomab showed grade 3 or 4 CRS in up to 9% of patients, suggesting that the true incidence of cardiotoxicity may be higher than that observed in clinical trials. 17 Overall, the rates of CRS with BiTE therapy have ranged from 0% to 20%. 18 , 19 In the TOWER trial, acute coronary syndrome was reported in 0.4% of patients. Additionally, a case of fatal HF was reported after blinatumomab treatment in a child with acute lymphoblastic leukemia. 2

There are no reports of CRS with TIL therapy. However, several studies have reported hypotension and arrhythmias. In a single-center retrospective study of 43 patients undergoing TIL treatment for melanoma, 14% developed atrial fibrillation, 32% experienced shock requiring vasopressors, and there were no cases of cardiomyopathy or HF. 20

It is important to note that these data should not be interpreted as evidence of the absence of significant cardiotoxicity with BiTE and TIL therapies; rather, further studies with systematic surveillance for cardiotoxicity are needed in patients undergoing these treatments.

Timing of Cardiotoxicity

Although CRS can develop at any time and as long as CAR T cells persist in the circulation, it typically occurs early after CAR T-cell infusion with a median time of 2.2 days, with the highest risk for occurrence within the first 2 weeks. Cardiotoxicity similarly occurs early after administration of CAR T-cell administration, usually within the first 2 weeks. 10 , 21

Risk Factors

High-grade CRS, particularly grade ≥3 CRS, is a risk factor for cardiotoxicity. In a retrospective analysis of 145 patients, grade 3 CRS (HR: 8.42; P < 0.001) and grade 4 CRS (HR: 29.86; P < 0.001) were independent predictors of cardiotoxicity and MACE. 12 Similar findings have been reported in other retrospective studies. 8 , 10 Although CRS is a common side effect of CAR T-cell therapy, factors that increase in vivo CAR T-cell numbers, such as high disease burden, higher infused CAR T-cell dose, or high-intensity lymphodepletion regimens before CAR T-cell administration, have been associated with an increased risk for high-grade CRS. 21

Baseline cardiovascular risk factors and disease may also increase the risk for developing CAR T-cell–associated cardiomyopathy. In a retrospective study, patients who developed cardiomyopathy were older, were more likely to be on renin-angiotensin inhibitors and β-blockers at baseline (reflective of underlying risk factors), and had a greater prevalence of hyperlipidemia and coronary artery disease. Prior anthracycline or radiation exposure and a history of stem cell transplantation, commonly associated with the development of cardiomyopathy, were not associated with cardiotoxicity in this study. 10 Baseline renal insufficiency has also been identified as an independent risk factor for MACE. 12 As stated earlier, in studies based on adverse event reporting, cardiotoxicity appears to occur more frequently with axicabtagene-ciloleucel relative to tisagenlecleucel. However, these data should be interpreted with caution, as the true incidence of cardiotoxicity was not captured in these studies. 14

Pretherapy Evaluation

In the absence of evidence-based guidance, experts recommend a pretherapy cardiovascular examination, electrocardiography, and echocardiography in patients receiving T-cell therapies. Further evaluation for underlying obstructive coronary artery disease or other structural heart disease may be required in select patients with cardiovascular symptoms, impaired exercise capacity, histories of cardiovascular disease, or multiple cardiovascular risk factors to ensure the ability to withstand the hemodynamic perturbations imposed by high-grade CRS. 9

Optimization of cardiovascular status and adjustment of medications may be necessary to minimize the risk for serious adverse events. For example, high-grade CRS is associated with hypotension, so antihypertensive medications may need to be down-titrated or discontinued temporarily. Similarly, given the increased risk for thrombocytopenia and bleeding, antiplatelet or antithrombotic medications may need to be adjusted on a case-by-case basis. 9

Diagnosis

All patients receiving T-cell therapies should undergo blood pressure monitoring. In our view, for patients with grade ≥2 CRS, hemodynamic instability, or any concerning symptoms for cardiotoxicity, electrocardiography, echocardiography, and measurements of cardiac biomarkers, including cardiac troponin and brain natriuretic peptide, should be obtained. Although troponin elevation has been associated with MACE, 8 routine surveillance with troponin may not be helpful in the absence of clinical concern. In contrast, surveillance echocardiography in patients with grade ≥2 CRS should be considered, regardless of symptoms, given that approximately 10% of patients may develop cardiomyopathy with downstream implications. 9 Neurotoxicity is also a common adverse effect of CAR T-cell therapy, and cardiovascular evaluation should be considered in those who develop neurotoxicity.

A thorough work-up should be performed to evaluate for other possible or contributory etiologies of hemodynamic instability, including sepsis, tumor lysis syndrome, pulmonary embolism, or primary cardiac events.

Management

As patients with grade ≥2 CRS are more likely to develop cardiotoxicity, 8 , 10 , 12 a generalized approach to the management of CRS is used to mitigate cardiotoxicity with additional specific cardiac interventions as needed. In addition to intravenous fluids, vasopressors, and oxygen supplementation as needed, the IL-6 antagonist tocilizumab or siltuximab (not Food and Drug Administration approved for the management of CRS) should be considered for moderate to severe CRS. 8 , 9 A shorter time to tocilizumab administration from the onset of CRS is associated with a lower risk for MACE. 8 Repeated doses of these agents may be required, and steroids are recommended in cases that are refractory to IL-6 antagonists. Furthermore, patients with grade 3 or 4 CRS should be transferred to intensive care for continuous monitoring, management of arrhythmias and circulatory shock, and provision of noninvasive positive pressure or mechanical ventilation as needed.

Preclinical studies have demonstrated the utility of the IL-1R antagonist anakinra alone and in combination with tocilizumab in the management of CAR T-cell therapy–associated CRS. 22 Case reports have also demonstrated its utility in patients with multiple myeloma receiving anti-BCMA CAR T-cell therapy. 23 These observations suggest that IL-1 inhibition may be a valuable adjunct in the management of CRS following CAR T-cell therapy.

CAR T-cell therapy has been associated with an increased risk for thrombosis and bleeding, in part related to disseminated intravascular coagulation in the context of CRS, and the risk for bleeding is increased in patients with pre-existing thrombocytopenia and neurotoxicity. 24 Therefore, in patients who develop acute coronary syndromes or atrial arrhythmias with CAR T-cell therapy, the risks and benefits of anticoagulation must be considered carefully.

Prognosis

The prognosis of patients who develop T-cell therapy–associated cardiotoxicity is not well studied given patient heterogeneity and small sample sizes. In a retrospective study, among the 10% of patients who developed new or worsening cardiomyopathy, LVEF improved in 75% with supportive care, with only one-half returning to normal LVEFs after about 6 months of follow-up. 10 Additionally, those who developed cardiomyopathy had a higher need for vasopressor support (42% vs 8%; P = 0.004) and mechanical ventilation (25% vs 3%; P = 0.014) relative to those without cardiomyopathy. 10

In retrospective cohort studies of adults undergoing CAR T-cell therapy, the incidence of death attributed to cardiotoxicity was 1.4% to 4.3%. 8 , 11 In addition, in a cross-sectional study leveraging Food and Drug Administration Adverse Events Reporting System data, all-cause mortality was increased in patients with cardiovascular adverse events (30.1% vs 21.1%). 14

Long-term cardiovascular effects of T-cell therapies are poorly characterized, and prospective studies are needed. It is possible that persistent immune system alteration by circulating cells may pose a higher risk for developing metabolic syndrome, hypertension, vascular disease, and cardiomyopathy after a latent period.

Future Directions

There is growing enthusiasm to explore the utility of genetically engineered T cells in the treatment of solid tumors and autoimmune diseases and even to prevent myocardial fibrosis in patients with HF. As the indications and availability of T-cell therapies increase, so do the concerns for potential cardiotoxicity. A multidisciplinary approach to the management of patients on novel immunotherapies is needed to optimize outcomes, and cardio-oncologists play a vital role in the comprehensive care of these patients.

Funding Support and Author Disclosures

Dr Nohria is supported by the Catherine Fitch Fund and the Gelb Master Clinician Fund at Brigham and Women’s Hospital; and is a consultant for AstraZeneca, Boehringer Ingelheim, Bantam Pharmaceuticals, and Takeda Oncology. Dr Zaha has received support from the Cancer Prevention Research Institute of Texas (RP180404). Dr Yang has received research funding from CSL Behring, Boehringer Ingelheim, and Eli Lilly; and has received consulting fees from Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Acknowledgment

The authors thank Dr Ashley Stein-Merlob for her assistance in data collection and assistance in assembling figures for this paper.

Footnotes

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center .

References

1. June C.H., Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379:64–73. doi: 10.1056/NEJMra1706169.

2. Kantarjian H., Stein A., Gökbuget N., et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–847. doi: 10.1056/NEJMoa1609783.

3. Wang S., Sun J., Chen K., et al. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med. 2021;19:140. doi: 10.1186/s12916-021-02006-4.

4. Einsele H., Borghaei H., Orlowski R.Z., et al. The BiTE (bispecific T-cell engager) platform: Development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer. 2020;126:3192–3201. doi: 10.1002/cncr.32909.

5. Cameron B.J., Gerry A.B., Dukes J., et al. Identification of a titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 2013;5 doi: 10.1126/scitranslmed.3006034.

6. Neelapu S.S., Tummala S., Kebriaei P., et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62. doi: 10.1038/nrclinonc.2017.148.

7. Lee D.W., Santomasso B.D., Locke F.L., et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625–638. doi: 10.1016/j.bbmt.2018.12.758.

8. Alvi R.M., Frigault M.J., Fradley M.G., et al. Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T) J Am Coll Cardiol. 2019;74:3099–3108. doi: 10.1016/j.jacc.2019.10.038.

9. Ganatra S., Carver J.R., Hayek S.S., et al. Chimeric antigen receptor T-cell therapy for cancer and heart: JACC Council perspectives. J Am Coll Cardiol. 2019;74:3153–3163. doi: 10.1016/j.jacc.2019.10.049.

10. Ganatra S., Redd R., Hayek S.S., et al. Chimeric antigen receptor T-cell therapy-associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma. Circulation. 2020;142:1687–1690. doi: 10.1161/CIRCULATIONAHA.120.048100.

11. Alí A., Boutjdir M., Aromolaran A.S. Cardiolipotoxicity, inflammation, and arrhythmias: role for interleukin-6 molecular mechanisms. Front Physiol. 2019;9:1866. doi: 10.3389/fphys.2018.01866.

12. Lefebvre B., Kang Y., Smith A.M., Frey N.V., Carver J.R., Scherrer-Crosbie M. Cardiovascular effects of CAR T cell therapy. A retrospective study. J Am Coll Cardiol CardioOnc. 2020;2:193–203. doi: 10.1016/j.jaccao.2020.04.012.

13. Salem J.-E., Ederhy S., Lebrun-Vignes B., Moslehi Javid J. Cardiac events associated with chimeric antigen receptor T-cells (CAR-T) J Am Coll Cardiol. 2020;75:2521–2523. doi: 10.1016/j.jacc.2020.02.070.

14. Guha A., Addison D., Jain P., et al. Cardiovascular events associated with chimeric antigen receptor T cell therapy: cross-sectional FDA adverse events reporting system analysis. Biol Blood Marrow Transplant. 2020;26:2211–2216. doi: 10.1016/j.bbmt.2020.08.036.

15. Burstein D.S., Maude S., Grupp S., Griffis H., Rossano J., Lin K. Cardiac profile of chimeric antigen receptor T cell therapy in children: a single-institution experience. Biol Blood Marrow Transplant. 2018;24:1590–1595. doi: 10.1016/j.bbmt.2018.05.014.

16. Munshi N.C., Anderson L.D., Shah N., et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384:705–716. doi: 10.1056/NEJMoa2024850.

17. Apel A., Ofran Y., Wolach O., et al. Safety and efficacy of blinatumomab: a real world data. Ann Hematol. 2020;99:835–838. doi: 10.1007/s00277-019-03854-0.

18. Topp M.S., Kufer P., Gökbuget N., et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493–2498. doi: 10.1200/JCO.2010.32.7270.

19. Jung S.H., Lee S.R., Yang D.H., et al. Efficacy and safety of blinatumomab treatment in adult Korean patients with relapsed/refractory acute lymphoblastic leukemia on behalf of the Korean Society of Hematology ALL Working Party. Ann Hematol. 2019;98:151–158. doi: 10.1007/s00277-018-3495-2.

20. Fradley M.G., Damrongwatanasuk R., Chandrasekhar S., Alomar M., Kip K.E., Sarnaik A.A. Cardiovascular toxicity and mortality associated with adoptive cell therapy and tumor-infiltrating lymphocytes for advanced stage melanoma. J Immunother. 2021;44:86–89. doi: 10.1097/CJI.0000000000000341.

21. Ganatra S., Parikh R., Neilan T.G. Cardiotoxicity of immune therapy. Cardiol Clin. 2019;37:385–397. doi: 10.1016/j.ccl.2019.07.008.

22. Norelli M., Camisa B., Barbiera G., et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24:739–748. doi: 10.1038/s41591-018-0036-4.

23. Jatiani S.S., Aleman A., Madduri D., et al. Myeloma CAR-T CRS management with IL-1R antagonist anakinra. Clin Lymphoma Myeloma Leuk. 2020;20:632–636.e1. doi: 10.1016/j.clml.2020.04.020.

24. Johnsrud A., Craig J., Baird J., et al. Incidence and risk factors associated with bleeding and thrombosis following chimeric antigen receptor T-cell therapy. Blood Adv. 2021;5:4465–4475. doi: 10.1182/bloodadvances.2021004716.

25. Lee D.W., Kochenderfer J.N., Stetler-Stevenson M., 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;385:517–528. doi: 10.1016/S0140-6736(14)61403-3.

26. Maude S.L., Laetsch T.W., Buechner J., et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–448. doi: 10.1056/NEJMoa1709866.

27. Locke F.L., Ghobadi A., Jacobson C.A., et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20:31–42. doi: 10.1016/S1470-2045(18)30864-7.

28. Schuster S.J., Bishop M.R., Tam C.S., et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45–56. doi: 10.1056/NEJMoa1804980.

29. Shalabi H., Sachdev V., Kulshreshtha A., et al. Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies. J Immunother Cancer. 2020;8 doi: 10.1136/jitc-2020-001159.

30. Wang M., Munoz J., Goy A., et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331–1342. doi: 10.1056/NEJMoa1914347.

31. Abramson J.S., Palomba M.L., Gordon L.I., et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396:839–852. doi: 10.1016/S0140-6736(20)31366-0.

32. Qi K., Yan Z., Cheng H., et al. An analysis of cardiac disorders associated with chimeric antigen receptor T cell therapy in 126 patients: a single-centre retrospective study. Front Oncol. 2021;11 doi: 10.3389/fonc.2021.691064.

33. Brammer J.E., Braunstein Z., Katapadi A., et al. Early toxicity and clinical outcomes after chimeric antigen receptor T-cell (CAR-T) therapy for lymphoma. J Immunother Cancer. 2021;9 doi: 10.1136/jitc-2020-002303.

34. Foà R., Bassan R., Vitale A., et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383:1613–1623. doi: 10.1056/NEJMoa2016272.

35. Couturier M.A., Thomas X., Raffoux E., et al. Blinatumomab + ponatinib for relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia in adults. Leuk Lymphoma. 2021;62:620–629. doi: 10.1080/10428194.2020.1844198.

36. Chandran S.S., Somerville R.P.T., Yang J.C., et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol. 2017;18:792–802. doi: 10.1016/S1470-2045(17)30251-6.

37. Sarnaik A.A., Hamid O., Khushalani N.I., et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39:2656–2666. doi: 10.1200/JCO.21.00612.