CAR-T Therapy Can Be a Useful Treatment Modality for More Than Just Hematologic Malignancies.

Текст сохранён. Часть иллюстраций пока доступна только в первоисточнике; загрузка будет проверена повторно.

Overview of CAR-T

T cells and antibodies are the primary effectors of acquired immunity. The T-cell receptor (TCR) recognizes complexes of antigen peptides and the self-major histocompatibility complex (MHC), and it plays a crucial role in highly personalized biological defense, thus making it challenging to develop universal “off-the-shelf” therapies. Currently, the U.S. Food and Drug Administration has approved only therapies targeting antigen+MHC complexes, specifically T cell engagers targeting gp100+HLA-A*02:01, for metastatic uveal melanoma. In contrast to TCR, antibodies directly recognize antigens, and numerous chimeric or recombinant antibody drug formulations have emerged. The affinity of antibodies or B cell receptors for antigens is approximately 1,000 times greater than that of TCRs, surpassing their binding strength. However, their ultimate effector action relies on antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity ( 1 ), and the cytotoxic effect of antibody drugs alone is not strong. To overcome this drawback, various antibody-drug conjugates (ADCs) have been developed. Chimeric antigen receptor-T-cell (CAR-T) therapy replaces complex intrinsic recognition by TCRs with recognition by antibodies, and introduces a construct that links TCR signaling molecules in series into T cells collected from patients beforehand using lentiviruses or retroviruses. From the perspective of antibody formulations, this can be considered the ultimate ADC, where the drug proliferates autonomously. Even when sufficient effects cannot be achieved using antibodies alone, the CAR-T technique can lead to the anticipated effects ( 2 ). The specific construct consists of the following, in sequential order from extracellular recognition sites: a single-chain variable fragment (scFv) formed by linking the heavy chain variable region and light chain variable region of the antibody in series, a transmembrane domain, co-stimulatory domains (CD28 or 4-1BB), and T cell signaling domains (CD3ζ chain) ( Fig. 1 ) ( 3 ). Currently, the marketed CAR-T cell therapies are second-generation therapies that utilize either CD28 or 4-1BB as costimulatory molecules. Third-generation CAR-T cells include both CD28 and 4-1BB, whereas the fourth and fifth generations introduce various signaling molecules to enhance activation efficiency. However, excessive stimulation via TCR signaling may lead to the early exhaustion of T cells; therefore, the search for an ideal construct continues.

Lymphodepletion (LD) therapy should be performed before CAR-T cell therapy to improve its effectiveness ( 4 ). Once the lymphocyte counts decrease due to LD, homeostatic proliferation (HP) mechanisms come into play to restore them to their original levels. The essence of HP lies in the release of cytokines such as interleukin (IL)-7 and IL-15 into the microenvironment necessary for lymphocyte proliferation and maintenance. This enabled the administered CAR-T cells to proliferate, thus leading to stable clinical effects. The most common regimens for LD therapy include fludarabine (FLU) and cyclophosphamide (CY) (FLU/CY regimen). A washout period of 2-5 days is typically required between the final administration of drugs, such as CY and CAR-T cell infusion. As FLU is only covered by insurance for lymphoid malignancies and hematopoietic cell transplants, caution is required during clinical trials for the application of CAR-T cell therapy beyond hematologic malignancies, which is the theme of this study.

When implementing CAR-T cell therapy, it is essential to be proficient in managing specific complications, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHT), and infection prevention associated with CAR-T cell therapy. In particular, owing to the initial high frequency of CRS when CAR-T cell therapy begins, the presence of an intensive care unit equipped to manage CRS has become a requirement for CAR-T cell administration. Recently, grading systems for CRS have been established, and the early administration of tocilizumab, an IL-6 receptor antibody, or dexamethasone has proven to be effective in managing CRS. ICANS, a neurological disorder that occurs after CAR-T cell therapy, presents with features such as dysgraphia and an inability to perform calculations like 100-10, 90-10, etc. Steroid administration is generally prioritized over tocilizumab for ICANS, because tocilizumab is usually ineffective. Recently, the TGFβ-activated kinase-1-NF-κB-p38 MAPK pathway in microglial cells was identified to play a crucial role in the mechanism of ICANS ( 5 ). ICAHT is a condition in which pancytopenia persists after CAR-T cell therapy. This increases the risk of infection and may necessitate a prolonged hospital stay.

The use of T cells as effectors became evident when CAR-T cell therapy demonstrated significant therapeutic effects, even in hematologic malignancies unresponsive to existing treatments. However, CAR-T cell therapy has unavoidable complexities and economic burdens associated with T cell collection and genetic manipulation. Therefore, the concept of creating drug formulations that combine target-specific antibodies with anti-CD3 antibodies has emerged. These drugs aim to achieve effects similar to those of CAR-T cell therapy by forcibly bridging target and T cells within the body. These drugs, known as bi-specific T cell engagers (BiTE Ⓡ , Amgen, Tokyo, Japan) or dual-specificity antibodies, can be administered as conventional drugs, offering simplicity. However, similar to CAR-T cell therapy, they can lead to complications, such as CRS and ICANS. Discussions regarding the advantages and disadvantages of CAR-T cell therapy versus dual-specificity antibodies and the optimal sequence of their use are ongoing in the field of hematological malignancies.

CAR-T Cell Therapy for Solid Tumors

CAR-T cell therapy is not limited to hematological malignancies, when the antibody is responsible for target recognition. Several ADCs have been used clinically as extensions of this concept in the field of solid tumors. Clinical trials of CAR-T cell therapy for nearly all tumors are predominantly conducted in the United States and China ( Fig. 2 ) ( 6 ). Most were still in the early stages of phase I. As of May 2024, among the clinical trials registered at ClinicalTrials.gov, only anti-carcinoembryonic antigen (CEA)-CAR-T cells for liver metastasis-positive pancreatic cancer have progressed to phase IIb ( NCT04037241 ). Detailed progress information is limited because many trials are still ongoing, which thus makes it premature to comment on their effectiveness. However, as this review aimed to stimulate interest in the various applications of CAR-T cell therapy, there may be more discussion on its effectiveness than on its safety.

Surprisingly, the most impressive report on CAR-T cell therapy for solid tumors was for brain tumors. Majzner et al. ( 7 ) conducted a Phase I trial ( NCT04196413 ) of CAR-T cell therapy targeting disialoganglioside (GD2) for a specific pediatric brain tumor, diffuse midline glioma. This tumor is known to have a histone H3 K27M mutation and high GD2 expression, leading to a first-in-human trial following mouse experiments ( 8 ). Clinical improvements in symptoms and imaging findings were observed in three out of four patients ( Fig. 3 ). A phase I trial administering CAR-T cells targeting epidermal growth factor receptor to nine patients with advanced or recurrent lung cancer was conducted. The results showed one partial response (PR), six stable diseases (SD), and two progressive diseases (PD) ( 9 ). A phase I trial administering CAR-T targeting Claudin18.2 to 37 previously treated patients with gastric cancer was conducted, resulting in an objective response rate of 48.6% and 6-month response rate of 44.8% ( 10 ). Four phase I trials have been conducted for pancreatic cancer. In the first trial, CAR-T cells targeting mesothelin were administered to six patients, resulting in SD in two patients ( NCT01897415 ). The second trial administered CAR-T targeting CD133 to 23 patients with CD133-positive tumors, including pancreatic cancer, resulting in two partial responses (PR), three stable diseases (SD), and two progressive diseases (PD) in seven patients with pancreatic cancer ( NCT02541370 ) ( 11 ). The third trial administered CAR-T cells targeting EGFR to 16 patients, thus resulting in four PR, eight SD, and two losses (NCT0869166) ( 12 ). The fourth trial administered CAR-T cells targeting HER-2 to 11 patients, including two patients with pancreatic cancer, resulting in SD in both patients with pancreatic cancer ( 13 ). For hepatocellular carcinoma, a phase I trial administering CAR-T cells targeting GPC3 along with IL-7 and CCL19 was conducted in four patients. In one patient who received the direct tumor administration of CAR-T cells, complete tumor disappearance was observed 30 days later ( NCT03198546 ) ( 14 ). For colorectal cancer, a phase I trial administering CAR-T cells targeting CEA to ten patients with metastatic treatment-refractory colorectal cancer was conducted, resulting in SD in seven patients ( NCT02349724 ). The CAR-T cell therapy efficacy is limited in renal cell carcinoma, ovarian cancer, and prostate cancer ( 15 ). Almost all clinical trials involving humans have been conducted in China.

Traditionally, solid tumors have been known to be less responsive to immunotherapy than hematologic malignancies for several reasons: 1) tumor cells form a more heterogeneous population, making it difficult to identify effective tumor antigens; 2) CAR-T cells have limited physical infiltration into the tumor site; and 3) the development of an immunosuppressive tumor microenvironment (TME) surrounding the tumor is noted ( 16 , 17 ). Regarding point 1, currently envisaged antigens include EGFR, HER2, mesothelin, GD2, which are also expressed in normal cells, potentially leading to side effects. The target antigens for CAR-T cell therapy against hematologic malignancies currently on the market are CD19, CD22, and B-cell maturation antigen (BCMA), which are also expressed in normal B cells and plasma cells. However, this drawback is overcome by replenishment with immunoglobulin products.

Regarding point 2, strategies such as the co-expression of chemokine receptors that induce T-cell migration with CAR-T cells or the introduction of heparinase to disrupt the extracellular matrix that impedes CAR-T cell infiltration are being considered ( Fig. 4, left ). Regarding point 3, tumor-associated macrophages, regulatory T cells (Tregs), myeloid-derived suppressor cells, and immunosuppressive cytokines, such as TGF-β, IL-10, and IL-4, are known components. Strategies to overcome this mechanism include enhancing CAR-T cell activity through activation of cytokines, cytokine receptors, or dominant-negative receptors for inhibitory factors. Programmed cell death protein 1/programmed death-ligand 1 inhibition is a well-known clinical approach for overcoming the TME. In the future, combinations of CAR-T cell therapy with immune checkpoint inhibitors or CAR-T cells incorporating PD-1/PD-L1 inhibition should be considered, especially the latter, which is theoretically expected to have fewer immune-related adverse events owing to the limited systemic effects of PD-1/PD-L1 inhibition ( Fig. 4, right ) ( 18 ).

CAR-T Therapy for Autoimmune Diseases

B cell activation plays a crucial role in the pathophysiology of autoimmune diseases. The effectiveness of rituximab (RTX) as a therapeutic target for B cells was demonstrated in rheumatoid arthritis (RA) in 2004 ( 19 ). In the 2024 Guidelines for the Management of Rheumatoid Arthritis by the Japan College of Rheumatology, RTX is conditionally recommended for patients with RA showing an inadequate response to conventional disease-modifying antirheumatic drugs, including methotrexate (MTX), and moderate or high disease activity. However, their effectiveness is not necessarily conclusive. Moreover, randomized phase II/III trials of RTX for systemic lupus erythematosus (SLE) failed to demonstrate its efficacy ( 20 ). One explanation for the inadequate efficacy of RTX is that while it efficiently kills B cells in the bloodstream, its efficacy against tissue-resident B cells is insufficient ( 21 - 23 ). However, in hematology, CAR-T cell therapy for B-cell malignancies has demonstrated sufficient efficacy, even in cases of relapse or nonresponse following first-line treatment, including RTX. This suggests that CAR-T cell therapy could offer deeper B-cell depletion than RTX, leading to the idea of using CAR-T cell therapy for autoimmune diseases. CAR-T cell therapy for autoimmune diseases has been spearheaded by a group from Erlangen University, Germany. The first in-human case reported in the New England Journal of Medicine in 2021 involved a 20-year-old patient with treatment-resistant SLE. Without any significant complications, the treatment resulted in complete clinical remission of symptoms, disappearance of autoantibodies, and successful cessation of all immunosuppressive therapies, including steroids, marking a significant success ( 22 ). Subsequently, the Erlangen group administered CAR-T cell therapy to five cases of SLE, including the present case, and reported in Nature Medicine in 2022 that all patients could discontinue immunosuppressive drugs ( 23 ). The CAR-T cell therapy target was further expanded and administered to 15 patients with autoimmune diseases, and the details were reported in the NEJM in February 2024 ( 24 ). As this is currently the most comprehensive report, it is discussed below:

CD19-CAR-T cells, prepared for research purposes, were administered to 15 patients with autoimmune diseases (eight patients with SLE, three patients with myositis, and four patients with systemic sclerosis). The method for creating CAR-T cells involved the following steps: 1) lymphocyte collection on day -13 (with CAR-T cell administration day designated as day 0); 2) enrichment of CD3-positive cells from CD4 + and CD8 + cells without freezing in the presence of IL-7 and IL-15; and 3) gene transfer using lentiviral vectors under CD3 and CD28 stimulation. The construct comprised a mouse-derived anti-CD19 antibody scFv binding to human CD19 exon 4, a tumor necrosis factor receptor superfamily transmembrane domain, CD3ζ, and co-stimulatory factor 4-1BB. Prior to CAR-T cell administration, LD was administered using the FLU/CY regimen (FLU 25 mg/m 2 /day on days 5 and 4, and 3+CY 1,000 mg/m 2 /day on day -3), similar to that for hematologic tumors. Premedication included only antihistamines and acetaminophen, and the CAR-T cell dose was 1×10 6 /kg. In this trial, immunosuppressive agents targeting T cells were discontinued before lymphocyte collection and the steroid dose was reduced to ≤10 mg/day of prednisolone. The median duration of B cell depletion was 112±47 days. All patients with SLE achieved remission according to the Definition of Remission in SLE criteria. Patients with myositis achieved a normalization of their muscle enzymes and met the Major Clinical Response Criteria of the American College of Rheumatology-European League Against Rheumatism, and all patients with systemic sclerosis showed a decrease in the European Scleroderma Trials and Research Group activity index. Immunosuppressive agents were discontinued in all the 15 patients.

The noteworthy findings from the analysis of CAR-T cell therapy for SLE include the following: 1) approximately 100 days after CAR-T cell administration, B cells begin to recover, showing a phenotype characteristic of naive B cells ( Fig. 5 ); and 2) while autoantibodies such as dsDNA antibodies become negative following CAR-T cell therapy, the titers of antiviral antibodies acquired from vaccinations administered prior to CAR-T cell treatment remain largely unchanged. This finding suggests that autoantibodies are produced by CD19-positive memory B cells, whereas viral antibodies are produced by long-lived plasma cells that are CD19-negative ( 25 ).

As reported in NEJM in 2024, CAR-T cell therapy for dermatomyositis, specifically anti-synthetase syndrome, was reported by Müller et al. in the Erlangen group ( 26 ) in March 2023 in Lancet, and by Pecher et al. from the University of Tübingen ( 27 ) in June 2023 in JAMA. The case from the Erlangen group involved a 41-year-old male presenting with elevated muscle enzyme levels and magnetic resonance imaging (MRI) findings indicative of myositis, interstitial pneumonia, Raynaud's symptoms, periorbital edema, and Jo-1 antibody positivity. He had previously received treatments, including steroids, RTX, immunoglobulin therapy, tacrolimus, and cyclophosphamide; however, he experienced recurrent remissions and exacerbations necessitating oxygen therapy. Following CAR-T cell administration, transient muscle pain, accompanied by a temporary increase in muscle enzyme levels, was observed. Subsequently, improvements in muscle symptoms, the disappearance of myositis on MRI, seroconversion to negative Jo-1 antibodies, a resolution of pneumonia, and a cessation of oxygen therapy were achieved, leading to remission without the need for immunosuppressive therapy. The case from the University of Tübingen involved a 41-year-old male with elevated muscle enzyme levels, muscle pain, MRI findings indicative of myositis and interstitial pneumonia. He had previously been treated with steroids, methotrexate, leflunomide, baricitinib, RTX, azathioprine, and immunoglobulin but was unresponsive. Following CAR-T cell administration, improvements in muscle pain, a restoration of muscle strength, an improvement in his respiratory function, and a normalization of blood test results were observed. The world's first case of CAR-T cell therapy for systemic sclerosis was also reported by Bergmann and colleagues from the Erlangen group ( 28 ). This case involved the fibrosis of the skin, lungs, and heart. Improvements in arthritis; Raynaud's symptoms; and fibrosis of the skin, heart, and joints were observed. It is worth considering whether such seemingly irreversible conditions can be improved by CAR-T cell therapy. In addition, there are other instances where CAR-T cells have been administered to humans for autoimmune diseases, such as the phase Ib/IIa trial reported by Granit et al. ( 29 ) involving 14 patients with severe myasthenia gravis and the physician-initiated phase I trial reported by Qin et al. ( 30 ) in 2023 in Signal Transduction and Targeted Therapy involving 12 patients with anti-Aquaporin 4 antibody-positive neuromyelitis optica. In these two clinical trials, CAR-T cells targeting BCMA, which is reimbursed for multiple myeloma, were employed rather than the CD19-targeted CAR-T cells used previously. BCMA is an antigen that is expressed during the differentiation of B cells into plasma cells. In the trial for severe myasthenia gravis, CRS and ICANS did not occur in any patient, and an improvement in the disease scores was observed. Notably, constructs using RNA instead of conventional DNA were used in this trial. In a trial of anti-AQP4 antibody-positive neuromyelitis optica, Grade 1-2 CRS occurred in all patients, and Grade 3 or higher hematological toxicity was observed. Seven of 12 patients (58%) developed infections. The symptoms improved in all patients, and no recurrence was observed in 11 patients.

To date, four review articles have been published on CAR-T cell therapy for autoimmune diseases. One, published by the Erlangen group ( 25 ) in Lancet in 2023, provides a clear description of this concept, which this review largely follows. A review article by Johnson et al. from Yale University ( 31 ), published in 2024 in Current Opinion in Rheumatology, provides a suitable overview of recent advancements from an objective standpoint. Daamen and Lipsky ( 32 ) pointed out that a series of reports lacks comparative trials. A review from Russia in 2024 ( 33 ) outlined CAR-T cell therapy and its disease characteristics.

CAR-T Therapy for Infectious Diseases

From a global perspective, infectious diseases, particularly those involving drug-resistant pathogens, pose significant challenges that must be addressed. If useful antibodies against individual pathogens are available, CAR-T cell therapy for infectious diseases can be considered as a natural extension. Specifically, ongoing projects include CAR-T cell therapies targeting viruses (such as human immunodeficiency virus (HIV), Epstein–Barr virus, cytomegalovirus, hepatitis B virus, hepatitis C virus, severe acute respiratory syndrome coronavirus 2) ( 34 ) and fungi ( Aspergillus ) ( 35 - 38 ). Mao et al. ( 38 ) constructed CAR-T cells targeting the HIV envelope glycoprotein and co-expressing CXCR5 for enhanced efficacy, which were administered to 18 HIV patients. The plasma viral load decreased by an average of 67.1% and persistent reductions in cell-associated HIV-1 mRNA levels were observed in 10 individuals.

CAR-T cell therapy for Aspergillus has been under consideration since the relatively early stages ( 39 ); however, as of 2024, there have been no reports of human trials. The most active reports were likely from Kumaresan et al. at the MD Anderson Cancer Center ( 36 ). They constructed a CAR-T construct using an Aspergillus -specific antibody in the targeting domain coupled with the CD8α transmembrane domain, 4-1BB, and CD3ζ. This construct was introduced into the cells by lentiviral gene transfer (for mouse administration, they attached to the C-terminus of the construct as a CAR expression monitor). These anti- Aspergillus CAR-T cells generate Th1 cytokines upon stimulation with Aspergillus hyphae, extending the survival of NSG mice with invasive pulmonary aspergillosis.

CAR-T Cell Therapy for Other Diseases

In addition to the aforementioned diseases, attempts have been made to introduce CAR constructs into Tregs to achieve specific immunosuppressive effects ( 40 ). Specifically, attempts have been made to administer FVIII-CAR-Treg targeting coagulation factor VIII in patients with hemophilia A, CEA-CAR-Treg targeting CEA in patients with asthma ( 41 ), HLA-A2-CAR-Treg targeting HLA-A2 in kidney ( NCT04817774 , NCT05987527 ) or liver ( NCT05234190 ) transplant patients for rejection prevention, and CD6-CAR-Treg targeting CD6 in graft-versus-host disease ( NCT05993611 ).

Conclusions

CAR-T cell therapy is currently thriving in the field of hematology and it now has various active clinical applications. Preclinical and early clinical trials are underway for the use of CAR-T cell therapy in solid tumors, autoimmune diseases, and infectious diseases. Such technological advancements have progressed rapidly, and by the time this brief review is published, new information is likely to have accumulated. The in vitro research not covered in this manuscript is burgeoning, highlighting the limited progress in actual clinical applications. Addressing the challenges of further CAR-T cell therapy development is essential. Healthcare economics is one such challenge, however. In the field of hematology, the cost-effectiveness of CAR-T cell therapy for malignant lymphomas in a 60-year-old cohort in the United States has been estimated at $68,000 to $99,000 per quality-adjusted life year (QALY), which is just below the general threshold of $100,000 per QALY considered acceptable for cost-effectiveness ( 42 ). In the realm of solid tumors, the market is larger; however, healthcare economics may need to be carefully considered when it comes to its introduction into clinical practice ( 43 ). Another issue to consider is the human factors. Currently, the actual clinical implementation of CAR-T cell therapy is mainly managed by hematologists, who may not necessarily be well-versed regarding solid tumors, immune disorders, or infections. For specialists of each solid tumor, the dramatic immune reactions associated with cell therapy may appear novel, and rheumatologists or infectious disease specialists may not routinely handle cancer chemotherapy. It is desirable to promote collaboration between hematology and other relevant fields, and to cultivate expertise in cell therapy, clinical oncology, immunology, and infectious diseases.

The author states that he has no Conflict of Interest (COI).

References

1. Taylor PA, Ehrhardt MJ, Roforth MM, et al. Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients. Blood 109: 1307-1315, 2007.

2. Hosen N, Matsunaga Y, Hasegawa K, et al. The activated conformation of integrin β 7 is a novel multiple myeloma-specific target for CAR T cell therapy. Nat Med 23: 1436-1443, 2017.

3. Wang JY, Wang L. CAR-T cell therapy: where are we now, and where are we heading? Blood Sci 5: 237-248, 2023.

4. Lickefett B, Chu L, Ortiz-Maldonado V, et al. Lymphodepletion - an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle. Front Immunol 14: 1303935, 2023.

5. Vinnakota JM, Biavasco F, Schwabenland M, et al. Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome. Nat Cancer. Forthcoming.

6. Han J, Zhang B, Zheng S, Jiang Y, Zhang X, Mao K. The progress and prospects of immune cell therapy for the treatment of cancer. Cell Transplant 33: 9636897241231892, 2024.

7. Majzner RG, Ramakrishna S, Yeom KW, et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603: 934-941, 2022.

8. Mount CW, Majzner RG, Sundaresh S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M + diffuse midline gliomas. Nat Med 24: 572-579, 2018.

9. Zhang Y, Zhang Z, Ding Y, et al. Phase I clinical trial of EGFR-specific CAR-T cells generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer patients. J Cancer Res Clinical Oncol 147: 3725-3734, 2021.

10. Qi C, Gong J, Li J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med 28: 1189-1198, 2022.

11. Wang Y, Chen M, Wu Z, et al. CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. Oncoimmunology 7: e1440169, 2018.

12. Liu Y, Guo Y, Wu Z, et al. Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: a phase I clinical trial. Cytotherapy 22: 573-580, 2020.

13. Feng K, Liu Y, Guo Y, et al. Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers. Protein Cell 9: 838-847, 2018.

14. Pang N, Shi J, Qin L, et al. IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J Hematol Oncol 14: 118, 2021.

15. Rojas-Quintero J, Díaz MP, Palmar J, et al. Car T cells in solid tumors: overcoming obstacles. Int J Mol Sci 25: 4170, 2024.

16. Chen T, Wang M, Chen Y, Liu Y. Current challenges and therapeutic advances of CAR-T cell therapy for solid tumors. Cancer Cell Int 24: 133, 2024.

17. Yuan G, Ye M, Zhang Y, Zeng X. Challenges and strategies in relation to effective CAR-T cell immunotherapy for solid tumors. Med Oncol 41: 126, 2024.

18. Najafi S, Mortezaee K. Modifying CAR-T cells with anti-checkpoints in cancer immunotherapy: a focus on anti PD-1/PD-L1 antibodies. Life Sci 338: 122387, 2024.

19. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350: 2572-2581, 2004.

20. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 62: 222-233, 2010.

21. Thurlings RM, Teng O, Vos K, et al. Clinical response, pharmacokinetics, development of human anti-chimaeric antibodies, and synovial tissue response to rituximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 69: 409-412, 2010.

22. Mougiakakos D, Krönke G, Völkl S, et al. CD19-Targeted CAR T cells in refractory systemic lupus erythematosus. N Engl J Med 385: 567-569, 2021.

23. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28: 2124-2132, 2022.

24. Müller F, Taubmann J, Bucci L, et al. CD19 CAR T-cell therapy in autoimmune disease - a case series with follow-up. N Engl J Med 390: 687-700, 2024.

25. Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases. Lancet 402: 2034-2044, 2023.

26. Müller F, Boeltz S, Knitza J, et al. CD19-targeted CAR T cells in refractory antisynthetase syndrome. Lancet 401: 815-818, 2023.

27. Pecher AC, Hensen L, Klein R, et al. CD19-targeting CAR T cells for myositis and interstitial lung disease associated with antisynthetase syndrome. JAMA 329: 2154-2162, 2023.

28. Bergmann C, Müller F, Distler JHW, et al. Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. Ann Rheum Dis 82: 1117-1120, 2023.

29. Granit V, Benatar M, Kurtoglu M, et al.; MG-001 Study Team . Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study. Lancet Neurol 22: 578-590, 2023.

30. Qin C, Tian DS, Zhou LQ, et al. Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results. Signal Transduct Target Ther 8: 5, 2023.

31. Johnson NM, Koumpouras F. Chimeric antigen receptors: “CARs” in the fast lane for rheumatology. Curr Opin Rheumatol 36: 176-183, 2024.

32. Daamen AR, Lipsky PE. Potential and pitfalls of repurposing the CAR-T cell regimen for the treatment of autoimmune disease. Ann Rheum Dis 83: 696-699, 2024.

33. Chasov V, Zmievskaya E, Ganeeva I, et al. Immunotherapy strategy for systemic autoimmune diseases: betting on CAR-T cells and antibodies. Antibodies (Basel) 13: 2024.

34. Eichholz K, Fukazawa Y, Peterson CW, et al. Anti-PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4 + T cells in germinal centers. J Clin Invest 134: e169309, 2024.

35. Nasiri-Jahrodi A, Barati M, Namdar Ahmadabad H, Badali H, Morovati H. A comprehensive review on the role of T cell subsets and CAR-T cell therapy in Aspergillus fumigatus infection. Hum Immunol 85: 110763, 2024.

36. Kumaresan PR, Wurster S, Bavisi K, et al. A novel lentiviral vector-based approach to generate chimeric antigen receptor T cells targeting Aspergillus fumigatus . mBio 15: e0341323, 2024.

37. Su H, Anthony-Gonda K, Orentas RJ, Dropulić B, Goldstein H. Generation of anti-HIV CAR-T cells for preclinical research. Methods Mol Biol 2807: 287-298, 2024.

38. Mao Y, Liao Q, Zhu Y, et al. Efficacy and safety of novel multifunctional M10 CAR-T cells in HIV-1-infected patients: a phase I, multicenter, single-arm, open-label study. Cell Discov 10: 49, 2024.

39. Kumaresan PR, Manuri PR, Albert ND, et al. Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci USA 111: 10660-10665, 2014.

40. Shu J, Xie W, Chen Z, Offringa R, Hu Y, Mei H. The enchanting canvas of CAR technology: unveiling its wonders in non-neoplastic diseases. Med 5: 495-529, 2024.

41. Skuljec J, Chmielewski M, Happle C, et al. Chimeric antigen receptor-redirected regulatory t cells suppress experimental allergic airway inflammation, a model of asthma. Front Immunol 8: 1125, 2017.

42. Choe JH, Yu T, Abramson JS, Abou-El-Enein M. Cost-effectiveness of second-line lisocabtagene maraleucel in relapsed or refractory diffuse large B-cell lymphoma. Blood Adv 8: 484-496, 2024.

43. Thavorn K, Thompson E, Kumar S, et al. Economic evaluations of CAR-T cell therapies for hematologic and solid malignancies: a systematic review. Value Health 27: 1149-1173, 2024.