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Abstract

Primary central nervous system lymphoma (PCNSL) is a very rare extranodal non-Hodgkin's lymphoma confined to the brain, eyes, spinal cord, and cerebrospinal fluid (CSF). This disease is highly aggressive. For decades, high-dose methotrexate-based induction regimens have been the standard treatment for PCNSL and have significantly improved patient overall survival (OS). However, some patients still experience disease recurrence or develop drug resistance. With a deeper understanding of the pathophysiology of PCNSL, various therapies, including CD20 monoclonal antibodies, Bruton's tyrosine kinase (BTK) inhibitors, immunomodulatory drugs, immune checkpoint inhibitors, phosphoinositide 3-kinase (PI3 K)/mammalian target of rapamycin(mTOR) inhibitors, and chimeric antigen receptor (CAR) -T cells are increasingly being applied and have demonstrated considerable efficacy. These therapies have paved the way for novel treatment strategies in PCNSL, representing a highly promising field. Investigating the mechanisms, specific targets, and signaling pathways, as well as interactions with the tumor microenvironment (TME), can provide a solid foundation for further exploration and potentially enhance the optimization of treatment approaches for PCNSL. This review seeks to explore the characteristics of the TME in PCNSL, elucidate the molecular mechanisms of various immunotherapies and targeted therapies, examine their interactions with the TME, and summarize the advancements in the research of PCNSL immunotherapy and targeted therapy.

Keywords

primary central nervous system lymphoma tumor microenvironment immunotherapy targeted therapy molecular mechanisms therapeutic prospects

Introduction

Primary central nervous system lymphoma (PCNSL) is a rare form of aggressive non-Hodgkin's lymphoma, which is limited to the brain, eyes, spinal cord, and the cerebrospinal fluid (CSF). Notably, it does not exhibit systemic involvement.¹ The incidence of this disease increases with age. Furthermore, the annual incidence of the disease is approximately 0.4 to 0.5 per 100,000 and is on the rise.²

Over 90% of PCNSL is histologically classified as diffuse large B cell lymphoma (DLBCL),³ which is characterized by an activated B-cell-like/nongerminal center (ABC/NGC) subtype. Notably, the survival rate of central nervous system (CNS) DLBCL patients is lower than that of DLBCL patients with organs outside the CNS.⁴

Additionally, high-dose methotrexate(HD-MTX)-based regimens have a high response rate and are widely accepted as the initial induction therapy of PCNSL.^5–7 Consolidation therapy following induction therapy includes autologous hematopoietic stem cell transplantation (ASCT) and whole-brain radiotherapy (WBRT).^6,7 However, HD-MTX-based regimens have the drawbacks of short remission time and a high short-term recurrence rate. Moreover, WBRT can induce severe late-onset neurotoxicity that increases with patient age and radiotherapy dose. In addition, approximately one-third of patients who receive first-line therapy do not respond to treatment and half of those who responded relapse.⁸ Therefore, there is an urgent need for new optimized protocols to improve the efficacy and prognosis of patients with PCNSL. In recent years, continuous progress in immunotherapy and targeted therapy has opened a new era in tumor treatment. CD20 monoclonal antibodies, Bruton's tyrosine kinase (BTK) inhibitors, immunomodulatory drugs, immune checkpoint inhibitors, phosphoinositide 3-kinase (PI3 K)/mammalian target of rapamycin(mTOR) inhibitors, and chimeric antigen receptor (CAR) -T cells have shown good efficacy in PCNSL, playing an antitumor role by regulating tumor microenvironment (TME); however, there is no definitive understanding of how they do so. Importantly, the feasibility and effectiveness of immunotherapy and targeted therapy are closely related to TME. Therefore, exploring the characteristics of the TME and its interaction with tumor cells provides a theoretical basis for exploring PCNSL immunotherapy and targeted therapy. Immune cells infiltration, modification, and evasion in the microenvironment play important roles in genesis, progression and metastasis of tumors. With the in-depth exploration of the TME of PCNSL, immunotherapy and targeted therapy have been gradually applied and shown excellent efficacy. These new therapies provide broad hope for the treatment of PCNSL. Therefore this article aimed to describe the TME of PCNSL, the interaction between the TME and tumor cells, and the mechanisms of some commonly used PCNSL immunotherapies and targeted therapies. This provides a theoretical basis for the treatment strategies of PCNSL and the exploration of new immunotherapies and targeted therapies.

Search Strategy

This article searched for relevant articles published in electronic publications (including PubMed, Web of Science, and the Cochrane Library) between January 2000 and October 2024 using the following keywords: (“ Primary central nervous system lymphoma “or” Primary CNS lymphoma “or” PCNSL “) and (“ Immunotherapy “or” Immunological therapy “and (“ Targeted therapeutic approach” or “Targeted therapy”). We also searched a list of references from identified articles to evaluate other potential studies. The included articles underwent screening based on their titles and abstracts. Those that did not meet our inclusion criteria were precluded from our further analysis.

Microenvironment of the Brain

The TME is a closely linked biological system composed of components surrounding the tumor cells, including immune cells, blood vessels, extracellular matrix and signaling factors.⁹ The TME comprises both tumor-promoting and tumor-suppressing components. The former includes tumor vessels, tumor-associated fibroblasts (CAFs), Th2 cells, and M2-like tumor-associated macrophages (TAMs), while the latter encompasses natural killer cells (NK), M1-like TAMs and Th1 cells. Dominance of tumor-promoting components leads to tumor progression. Traditionally, the brain was considered immune-privileged due to the blood-brain barrier and the absence of classical lymphatic tracts. However, recent studies have established that the CNS possesses its own immune system and is not “immune privileged”. In mammals, meningeal lymphatic vessels（MLVs） within the brain run alongside to the dural sinuses, facilitating the drainage of macromolecules and immune cells to the deep cervical lymph nodes (dCLN).^10–12 Studies using fluorescent tracer dyes have found that in healthy brains, soluble molecules and lymphocytes produced by the CNS are constantly circulating.¹³ These studies suggest that the CNS is not “immune privileged”, and that the immune system in some regions of the CNS may have functions similar to those of the peripheral nervous system. MLVs have drainage and immunological effects. The study found that after using chemical ablative drugs on the dorsal side, the transport of dendritic cells from the brain tumor to the dCLN was significantly reduced. The dorsal MLVs of mouse brain tumors undergo extensive remodeling, including lymphatic remodeling, inflammation and immune response changes, which play an important role in immunity. Thus, MLVs located on the dorsal side play a crucial role in brain tumor immune regulation and may be potential targets for brain tumor immunotherapy.¹⁴ The unique immune microenvironment of the brain provides a theoretical basis and a new strategy for immunotherapy.

Unique Microenvironment of PCNSL

Owing to the low incidence of PCNSL, there is a lack of substantial data for PCNSL TME; however, some relevant studies have explored this issue. PCNSL exhibits a distinctive TME (Figure 1). PCNSL cells are angiophilic, forming a “sleeve-like” pattern around blood vessels. one study,¹⁵ revealed that whole-cell RNA sequencing of the PCNSL transcriptome identified four major immune cells: B cells, T cells, macrophages, and dendritic cells, along with two types of stromal cells: oligodendrocytes and meningeal cells. These cell subsets interact within the TME, displaying significant heterogeneity. In PCNSL, macrophages are predominantly of the M2 type which supports tumor cell proliferation, contributes to TME angiogenesis, tumor cell infiltration, and metastasis, thus facilitating tumor progression. Conversely, M1 macrophages secrete pro-inflammatory factors, immune activators, and chemokines, fostering the acute inflammatory response, immune activation, and phagocytosis, thereby exerting an antitumor effect.¹⁶ Macrophage polarization to the M1 or M2 type is regulated and reversible. Thus, by promoting the transformation of M2 to M1 macrophages, tumor occurrence can be inhibited.¹⁷ B cells in PCNSL overexpress CD74, which interacts with macrophage migration inhibitory factor (MIF) as a MIF receptor, regulates interactions of B cells with T cells, dendritic cells, and macrophages, induces immune microenvironment disorder, and is a key target for immune regulation.¹⁵ Therefore, we believe antibodies against CD74 may represent a potential direction for immune-targeted therapy of PCNSL. In PCNSL cells, the number of activated CD8+ T cells is significantly higher than in lymph nodes, skin, or stomach. Activated CD8+ T cells exert tumor-killing effects dependent on their interactions with HLA class I molecules.¹⁸ Single-cell analysis revealed cellular composition, yet it lacked information on the spatial location of the TME. Subsequent research elucidated the spatial distribution characteristics and remodeling patterns of the PCNSL microenvironment, addressing the previous gap in spatial studies. The tumor-immune system interaction pattern categorized the TME into four primary types: “hot”, “invasive marginal exclusion (IME)”, “invasive marginal immunosuppression (IMS)” and “cold”. This study delineated the developmental trajectory of tumor cell clusters within the TME. Hot tumors marked the initiation of cell differentiation, with IMS serving as the transitional state of tumor differentiation. It ultimately diverged into two distinct differentiation endpoints: IME tumor and cold tumor. This evolutionary pattern of tumor cells was termed the “TME remodeling pattern”. Different states of the TME may elicit significantly diverse responses to drugs.¹⁹

Figure 1.

Tumor microenvironment (TME) of PCNSL. The TME consists of various cell types, including B cells, T cells, macrophages, dendritic cells, oligodendrocytes, and meningioma cells. Interactions among these cells contribute to the formation of the TME. CXCL13 promotes tumor cell proliferation and migration, while CXCL12 facilitates angiogenesis and induces the migration and proliferation of lymphoma cell lines. Additionally, CXCL12 stimulates the production of tumor necrosis factor, interleukin-1, and CCL5/RANTES in astrocytes and microglia. CCL19 plays a significant role in enhancing the retention of lymphoma cells in the central nervous system parenchyma. ECM, extracellular matrix; TNF, tumor necrosis factor; IL, interleukin; CCL, chemoattractant cytokine ligand; CXCL, CXC chemokine ligand; RANTES, regulated upon activation normal T cell expressed and secreted. Schematic created with CINEMA 4D.

A distinctive feature of PCNSL is that tumor cells are confined to the brain and do not spread to organs outside the brain. This selectivity is closely associated with the attraction and induction of chemokines. Chemokines, small cytokines or signaling proteins, facilitate chemotactic cell migration. They couple with chemokine receptors and promote lymphoma cells to cross the blood-brain barrier and disseminate within the brain, thus influencing PCNSL homing and proliferation. Vascular endothelial cells, astrocytes, microglia, and T cells in PCNSL express various chemokines and receptors.

Chemokine 1 (BCA-1, CXCL13) enables homing of B lymphocytes carrying the CXCL13 receptor CXCR5.²⁰ Notably, CXCL13 and CXCR5 are not expressed in normal brains. In contrast, they are expressed in malignant B lymphocytes and vascular endothelial cells in PCNSL. These findings suggest that in PCNSL, CXCL13 may promote the development of tumor cells and their chemotaxis to the CNS.²¹ In addition to the tumor-promoting effects of CXCL13, CXCL13 combined with IL-10 has high sensitivity and specificity for diagnosing CNS lymphoma.²² CXCL12 is widely expressed in hematological tumors and interacts with its receptor, CXCR4. Specifically, it can stimulate the movement and migration of bone marrow dendritic cells, B cells, and T cells.^23–25 Furthermore, neovascularization plays a significant role in tumor development as nutritional support and a metastatic pathway for tumor proliferation. Both in vivo and in vitro studies showed that CXCL12 and CXCR4 accelerated angiogenesis and affected embryonic blood vessels.²⁶ In a mouse model of non-Hodgkin's lymphoma, CXCL12 not only induced the migration and proliferation of lymphoma cell lines, but also activated tumor-promoting pathways such as Akt, ERK1/2, STAT3, p38 and c-Jun, which played a pro-tumor role.²⁷ Additionally, CXCR4 is linked to drug resistance in certain antitumor drugs. CXCR4 mutations can activate Akt and ERK signaling and promote lymphoma resistance to drugs such as ibrutinib, fludarabine, bortezomib, and bendamustine.²⁸ Overexpression of CXCR4 in DCLBL can confer resistance to rituximab-induced cytotoxicity, enabling lymphoma cells to evade its effects. Therefore, the use of CXCR4 antagonists may mitigate resistance and enhance the efficacy of rituximab.²⁹ Compared to normal brain tissue, CXCL12 expression in the vascular endothelium is significantly upregulated in PCNSL and is involved in various stages of PCNSL development.³⁰ CXCL12 can facilitate the passage of lymphocytes across the blood-brain barrier. Furthermore, regarding immunity, CXCL12 can stimulate astrocytes and microglia to produce tumor necrosis factor(TNF), interleukin-1, and chemoattractant cytokine ligand (CCL)5/regulated upon activation normal T cell expressed and secreted (RANTES), allowing these cell populations to interact with CXCR4-expressing cells and promote inflammation and immune response.³¹ Another signaling pathway, CCL19-CCR7, is involved in CNSL formation. CCL19 can enhance the retention of lymphoma cells in the CNS, thus promoting the formation of CNSL. Inhibition of CNSL development has been observed after the knockout of CCL19 or CCR7 in mice.³²

The TME of PCNSL regulates the occurrence and development of tumors. Immunotherapy exert antitumor effects by regulating immune cells, stromal cells and chemokines within the immune microenvironment. The efficacy of immunotherapy is closely related to the TME of PCNSL. Further investigation into the composition and function of PCNSL TME can provide more possibilities for immunotherapy.

Immunotherapy in PCNSL

A deepened understanding and ongoing research into PCNSL, encompassing tumor genesis, the TME, and the tumor molecular mechanisms of tumors, have ushered in a new era of immunotherapy and precisely targeted therapies for PCNSL. Current strategies for PCNSL include CD20 monoclonal antibodies, BTK inhibitors, immunomodulatory drugs, and CAR-T therapies. These approaches have demonstrated effective outcomes, particularly in relapsed/refractory (r/r) PCNSL, by precisely targeting and modulating immune responses to inhibit tumor growth. Table 1 displays data on the clinical application of these immunotherapies and targeted therapies in PCNSL. Figure 2 illustrates the mechanisms of action of various immune-targeted drugs used against PCNSL.

Figure 2.

Novel immunotargeted therapies for PCNSL and their mechanisms of action. The emerging therapeutic drugs exert their antitumor effects by targeting signaling pathways within the tumor and regulating the immune microenvironment. PD-1, programed death receptor 1; PD-L1, programed death ligand 1; AKT, protein kinase B; IRF4, interferon regulatory factor 4; mTOR, mammalian target of rapamycin; BTK, Bruton tyrosine kinase; BCR, B-cell receptor; TAA, tumor-associated antigen; NF-κB, nuclear factor-κB; BCR, B cell receptor. Schematic created with CINEMA 4D.

Table 1.

Summary of the Main Clinical Data on PCNSL Immunotherapies.

Author, year	Condition	Study type	Number of patients	Median age(years)	Regimen	Outcome
CD20 antibody
Batchelor 2011³³	r/r PCNSL	Phase II	12	64	R	ORR42%, mPFS 1.9 mo, mOS 20.9 mo
Nayak 2013³⁴	r/r PCNSL	Phase II	16	63	R + chemotherapy	ORR 36%, mPFS 1.6 mo,37-mo mOS NR
Fritsch 2017³⁵	PCNSL	Phase II	107	73	R + chemotherapy	mPFS 10.3 mo, mOS 20.7 mo
Ferreri 2022³⁶	PCNSL	Phase II	219	N/A	R + chemotherapy	7-year OS 53%
BTK inhibitor
Grommes 2017³⁷	r/r PCNSL/SCNSL	Phase I	20	69	Ibrutinib	ORR 77%, mPFS 4.6 mo, mOS 15 mo
Soussain 2019³⁸	r/r PCNSL/PVRL	Phase II	52	70	Ibrutinib	ORR 59%, mPFS 4.8 mo, mOS 19.2 mo
Chamoun 2017³⁹	r/r PCNSL/SCNSL	Retrospective	14	68	Ibrutinib	ORR 50%, mPFS NR, mOS NR
Chen 2020⁴⁰	PCNSL	Retrospective	11	56	Ibrutinib + MTX	ORR 81.8%, mPFS 7.4 mo
Narita 2021⁴¹	r/r PCNSL	Phase I/II	44	60	Tirabrutinib	0RR 64%, mPFS 2.9 mo
Bairey 2023⁴²	PCNSL	Phase II	20	72	HD-MTX Induction; Ibrutinib maintenance	2-year PFS 72.6%，2-year OS 89%
Yonezawa 2024⁴³	r/r PCNSL	Phase I/II	44	60	Tirabrutinib	3-year mOS NR
Lin 2024⁴⁴	r/r PCNSL	Phase II	34	62	Zanubrutinib+Cytarabine	0RR 64.7%, mPFS 4.5 mo, mOS 18 mo
IMids
Rubenstein 2018⁴⁵	r/r PCNSL/SCNSL	Phase I	14	66	Lenalidomide or lenalidomide + R	ORR 64%
Tun 2018⁴⁶	r/r PCNSL/PVRL	Phase I	25	Adults	Pomalidomide + DXM	ORR 48%, mPFS 5.3 mo
Vu 2019⁴⁷	PCNSL/SCNSL	Retrospective	13	77	Lenalidomide in maintenance	mPFS NR
PD-1 antibody
Nayak 2017⁴⁸	r/r PCNSL/PTL	Case report	5	64	Nivolumab	CR 4, PR 1，PFS 14–17 mo
Furuse 2017⁴⁹	r/r PCNSL	Case report	1	41	Nivolumab	CR
El-Tawab 2020¹⁴	r/r PCNSL	Case report	1	36	Nivolumab	CR, mPFS NR
CAR-T cells
Tu 2019⁵⁰	r/r PCNSL	case report	1	67	CD19-CD70 dual CAR-T	CR
Matthew 2019⁵¹	SCNSL	Retrospective	8	50	tisagenlecleucel
Li 2020⁵²	PCNSL/SCNSL	Phase I	5	39	CD19 CAR-T cells andCD22 CAR-T cells	CR (n = 1) PR (n = 4)
Wu 2021⁵³	PCNSL/SCNSL	Phase I	13	42	ASCT sequential CD19/22 CAR T cells	ORR 81.81%
Siddiqi 2021⁵⁴	PCNSL	Phase I	5	49	CD19 CAR-T cells	CR (n = 3) SD (n = 2)
Choquet 2024⁵⁵	PCNSL	Retrospective	25	68	CD19 CAR-T cells	mPFS 8.4 mo, mOS: 21.2 mo CR (n = 16, 64%) PR (n = 4, 16%)
mTOR inhibitor
Korfel 2016⁵⁶	r/r PCNSL	Phase II	37	70	Temsirolimus	ORR 54%, mPFS 2.1 mo, mOS 3.7 mo
Combination of drugs
Grommes 2017¹³	r/r PCNSL and SCNSL	Phase Ib	15	62	Ibrutinib + HD-MTX + R	4 of 6 patients showed a response
Lionakis 2017⁵⁷	ND and r/r PCNSL	phase Ib	18	66	Ibrutinib + DA-TEDDi-R	ORR 88.9%
Rubenstein 2018⁴⁵	r/r PCNSL	Phase I	14	66	Lenalidomide + R; lenalidomide maintenance	ORR 67%, mPFS 6 mo
Grommes 2019⁵⁸	r/r PCNSL/SCNSL	Phase Ib	15	62	Ibrutinib + MTX + R	ORR 80%，mPFS 9.2 mo, mOS NR
Ghesquiere 2019⁵⁹	r/r PCNSL/PVRL	Phase II	45	69	Lenalidomide + R	ORR 35.6%, mPFS 7.8 mo, mOS 17.7 mo

ORR, overall response rate; PFS, progression-free survival; mPFS, median progression-free survival; mOS, median overall survival; CR, complete response; PR, partial response; NR, not reached; SD, stable disease; Mo, month; PCNSL, primary central nervous system lymphoma; SCNSL, secondary central nervous system lymphoma; PVRL, primary vitreoretinal lymphoma; PTL, primary testicular lymphoma; r/r, relapsed/refractory; R, rituximab; IT Ritux, intrathecal rituximab; MTX, methotrexate; HD-MTX, high-dose methotrexate; CAR-T, chimeric antigen receptor T-cell immunotherapy; BTK i, BTK inhibitors; IMids, immunomodulatory drugs; DXM, dexamethasone; DA-TEDDi-R, etoposide, temozolomide, liposomal doxorubicin, dexamethasone, intrathecal cytarabinem; ASCT: autologous hematopoietic stem cell; N/A, not applicable.

CD20 Monoclonal Antibody

Rituximab, a first-generation human/murine chimeric monoclonal antibody, specifically binds to the CD20 antigen on the surface of B cells and induces their apoptosis. It is extensively used in treating lymphomas, and has become a cornerstone of many lymphomas treatments. As over 95% of PCNSL express CD20,⁶⁰ rituximab has been intensively studied for treating PCNSL. Several studies have explored rituximab's application in PCNSL, primarily using intravenous administration, while its intraventricular injection remains scarcely explored. In the multicenter randomized trial IELSG32, 219 patients with PCNSL were randomly divided into three groups: group A received methotrexate and cytarabine; group B received these agents plus rituximab; group C received group B's regimen plus thiotepa. The 7-year OS rates for groups A, B, and C were 21%, 37%, and 56%, respectively. The result showed that the 7-year OS of Group B was higher than that of Group A, indicating that the addition of rituximab benefited patient survival.³⁶ However, a HOVON 105 study showed that there was no significant difference between the addition or absence of rituximab based on MBPV chemotherapy regimens (methotrexate, carmustine, tiniposide, and prednisone), indicating that the addition of rituximab did not show significant benefits.⁶¹ Owing to its large molecular weight, rituximab cannot easily penetrate the blood-brain barrier, its concentration in the cerebrospinal fluid is only approximately 2% of the serum concentration, which limits the efficacy of rituximab.⁶² The efficacy of rituximab in induction therapy is controversial. However, most treatment centers continue adding intravenous rituximab to PCNSL treatment.

In addition to intravenous rituximab, intraventricular injection has been used in patients with PCNSL. In a phase Ι study, rituximab was shown to be safe and effective for both monotherapy with intraventricular injection and in combination with other drugs.⁶³ When rituximab was injected into the CSF, complement cascade activation was observed in the brain microenvironment.⁶⁴ This provided the theoretical foundation for immunotherapy in treating PCNSL via intraventricular injection of rituximab. However, given the limited research on ventricular injection of rituximab, its effective application in PCNSL deserves further investigation. Rituximab faces issues with low blood-brain barrier permeability. To address this limitation, rituximab can be combined with liposomes to create rituximab liposomes, which offer enhanced spatial stability, blood-brain barrier penetration, drug targeting, and therapeutic outcomes.⁶⁵

Overall, the impact of combining intravenous rituximab with high-dose chemotherapy on PCNSL prognosis remains controversial, potentially due to the blood-brain barrier limiting drug access to the CSF. Intraventricular administration of rituximab and liposomal rituximab may enhance the effect by increasing drug concentration at the blood-brain barrier. Given the limited data available, further research is necessary to confirm its impact on PCNSL prognosis. Future studies could explore methods to raise rituximab levels in the CSF, potentially enhancing its therapeutic effectiveness in PCNSL.

BTK Inhibitors

BTK is a key regulatory molecule in B cell proliferation and differentiation. It participates in several signal transmission pathways, including those of the B cell antigen receptor (BCR), chemokine receptor, and toll-like receptor. Activated BTK links BCR and toll-like receptors to the downstream nuclear factor-κB(NF-κB) signaling pathway, which plays crucial role in the development of B cell diseases.^66,67 Studies have shown that mutations in myeloid differentiation factor 88 (MYD88) and CD79 are common in PCNSL, and both are often seen together.⁵⁷ MYD88 is a key linker molecule in the toll-like receptor signaling pathway, and the formation of the MYD88-IRAK (IL-1 receptor associated kinase) signaling complex can promote the activation of the NF-κB signaling pathway. CD79B activates the downstream NF-κB signaling pathway, and CD79B mutation inhibits the negative regulation of the BCR signaling pathway, leading to chronic activation of the NF-κB signaling pathway.⁶⁸ Ibrutinib is a highly effective and selective small-molecule inhibitor that can irreversibly inhibit the activity of BTK by covalently binding to cysteine-481 (Cys-481) at the active site of BTK, inhibiting or downregulating downstream signaling molecules,⁶⁹ thereby inhibiting the malignant proliferation of tumor B cells and inducing cell apoptosis.⁷⁰ In addition, ibrutinib also regulates the TME. Studies have shown that ibrutinib can reduce the levels of various inflammatory cytokines and chemokines in chronic lymphocytic leukemia, downregulate the number of T cells, inhibit their activation and proliferation, disrupt the interaction between TAMs and tumor cells, and inhibit the secretion of CXCL13⁷¹; furthermore, it blocks the contact of tumor cells with pro-proliferative factors in the microenvironment, induces CD4+ T cells to differentiate into helper T cells (Th1), and enhances tumor immune surveillance.^72,73 Currently, ibrutinib has been successfully used to treat a variety of hematological tumors, including mantle cell lymphoma, chronic lymphocytic leukemia, and non-GCB DLBCL.^74,75 Notably, the efficacy of ibrutinib for PCNSL is related to intracranial drug concentration.⁷⁶ The blood-brain barrier can prevent some macromolecules from reaching diseased tissues, and a variety of specific transporters are expressed on the ependyma, transporting drugs from the epithelial cells of the blood-brain barrier to the peripheral blood circulation. This reduces the concentration of drugs in the CNS. Furthermore, different doses of ibrutinib have varying permeabilities in the CNS; approximately 560–840 mg of ibrutinib demonstrated better CNS permeability, with a cerebrospinal fluid/plasma ratio of 28.7% and a median time of crossing the blood-brain barrier of 0.29 h.⁷⁶ Patients with r/r PCNSL may exhibit some degree of blood-brain barrier disruption. The blood-brain barrier penetration and drug concentration of ibrutinib in r/r PCNSL were higher than those in newly treated PCNSL. Currently, more clinical trials of ibrutinib alone or in combination with other drugs for treating r/r PCNSL are showing good efficacy.^37,38,75 Grommes et al treated 20 patients with r/r PCNSL and secondary central nervous system lymphoma (SCNSL), including 13 patients with PCNSL and 7 patients with SCNSL, showing an overall response rate (ORR) of 77%, a median progression-free survival (PFS) of 4.6 months, and a median overall survival (MOS) of 15 months.³⁷ A study on r/r PCNSL and primary vitreoretinal lymphoma (PVRL) included 52 patients treated with 560 mg of ibrutinib once daily (28-day cycle). The results indicated an ORR of 59%, a median PFS of 4.8 months, and a median OS of 19.2 months.³⁸ Another prospective Phase 2 study evaluated the use of ibrutinib for maintenance in PCNSL. With a median follow-up of 29 months, 2-year PFS was 72.6% and 2-year OS was 89%.⁴² The second-generation BTK inhibitors tirabrutinib and zanubrutinib also demonstrated good efficacy in phase 1/2 studies. Forty-four patients with r/r PCNSL received 320 and 480 mg of tirabrutinib once daily, achieving an ORR of 64% and a median PFS of 2.9 months.⁴¹ A study, followed-up for three years, reported that MOS was not achieved, safety was acceptable, and quality of life was not significantly different.⁴³ Another study combining zanubrutinib with cytarabine in r/r PCNSL showed an overall remission rate of 64.7%, with a median PFS of 4.5 months and a OS of 18 months after 19 months of follow-up.⁴⁴

The efficacy of BTK inhibitors in PCNSL, particularly in r/r cases using first-generation ibrutinib and second-generation tirabrutinib has been confirmed. However, the duration of remission may be limited, suggesting that combination therapy may enhance efficacy. Further research could further investigate combining BTK inhibitors with other treatments to improve survival in PCNSL patients.

Immunomodulatory Drugs

Lenalidomide, a second-generation immunomodulatory drug, showed a higher response in ABC-type DLBCL than in GCB-type DLBCL.⁷⁷ PCNSL is primarily ABC-type DLCBL, establishing pathological foundation for treating PCNSL with lenalidomide. The malignant growth of ABC-type DLBCL cells primarily relies on two signaling pathways: the NF-κB proliferative signaling pathway, which drives the malignant proliferation of B cells, and the interferon (IFN) inhibitory signaling pathway, which induces apoptosis in B cells. IRF4 sustains the persistent activation of NF-κB and coordinates with IRF7 to suppress it apoptosis via the IFN pathway. Lenalidomide promotes the ubiquitination and degradation of IRF4, inhibiting NF-κB activation. It also liberates IRF7, which blocks the IFN pathway and encourages the apoptosis in the malignant clones of ABC subtype diffuse large B cells.⁷⁸ In lymphoma, lenalidomide regulates T cells, NK cells, and cytokines to exert immunoregulatory and tumor-killing effects. Interactions between T cells and tumor cells induce actin dysregulation at immune synapses, resulting in reduced immune synapse formation and decreased effector function, thereby causing tumor cells to resist immunity.⁷⁹ Notably, lenalidomide can improve immune synapse defects between CD8⁺ and CD4⁺ T cells and antigen-presenting cells, increasing CD8⁺ T cells cytotoxicity and CD4+ T cells helper cell effects. Furthermore, lenalidomide reduced the numbers of regulatory T cells and myeloid-derived suppressor cells in a mouse model.⁸⁰ In addition, it can upregulate NK cell numbers and enhance NK cells’ cytotoxicity as well as antibody-dependent cell-mediated cytotoxicity (ADCC) effect, which is indirectly mediated by T-cell production of IL-2. Cytokines play a critical role in immune regulation, tumor development, metastasis, and chemotherapy resistance. Lenalidomide can increase the expression of the anti-inflammatory cytokines IL-2, IL-8, IL-10, Interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), and decrease the expression of the inflammatory cytokines IL-1, IL-6, and IL-12 within the lymphoma microenvironment.^81,82 IL-6 can bind to receptors, transmit signals through the JAK-STAT, MAPK-ERK and PI3K-AKT pathways, activate transcription, and promote tumor progression. Lenalidomide reduced signal transduction in the mantle cell lymphoma microenvironment by downregulating IL-6 and signal transducer and activator of transcription 3 (STAT3) activities, thereby inhibiting mantle-cell lymphoma cell growth and inducing cell apoptosis.⁷⁹ (Table 2).

Table 2.

Effect of Immunomodulatory Drugs on Tumor Microenvironment.

Drug	Immune pathway	Potential effects on the immune microenvironment
Lenalidomide	T-cell effects	CD8+ T-effector cell activity↑
	T-cell effects	Cytotoxic CD8 + and helper CD4+ T cells↑
	NK-cell effects	Number and activity of NK cells↑
	NK-cell effects	ADCC effect↑
	Cytokine effect	Anti-inflammatory cytokines:IL-2, IL-8, IL-10, IFN-γ, TNF-α↑
	Cytokine effect	Inflammatory cytokines:IL-1, IL-6, IL-12, TNF-α↓
Pomalidomide	Macrophages	Converting the polarization state of macrophages from M2 to M1: M2-like macrophages↓, M1-like macrophages↑

ADCC, antibody-dependent cell-mediated; IL, interleukin; IFN-γ, Interferon-γ; TNF-α tumor necrosis factor-α.

Pomalidomide is a third-generation immunomodulatory drug with stronger CNS penetration than lenalidomide. It may play a role in treating CNSL through direct tumor cytotoxicity and the induction of changes in the TME. Pomalidomide has therapeutic activity against CNSL, inducing shifts in the TME, that convert the polarization state of TAMs from M2 to M1, thus significantly reducing M2 macrophages and increasing M1 macrophages, and mediating tumor apoptosis.⁸³

Regarding the use of immunomodulatory drugs for PCNSL, a phase 1 clinical study by Rubenstein et al included 14 cases of r/r CNSL. These patients received lenalidomide as maintenance therapy following HD-MTX or focal radiotherapy, with six maintaining response for ≥9 months and four for ≥ 18 months. Lenalidomide exhibits good CSF permeability and is effective as monotherapy for maintaining treatment of r/r CNSL.⁴⁵ Moreover, Tun et al examined the second-generation immunomodulatory drug pomadomide in a study of 25 patients with r/r PCNSL and PVRL treated with pomalidomide combined with dexamethasone, which showed an ORR of 48% and a median PFS of 5.3 months, demonstrating its efficacy against PCNSL.⁴⁶

Immune Checkpoint Inhibitors

Immune checkpoints are inhibitory molecules on immune cells that regulate immune responses, ensuring self-tolerance, preventing autoimmune reactions, and managing responses to tissue damage. They also enable tumor immune evasion. Primary immune checkpoints include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1. PD-1 is primarily expressed on T cells, but also B cells, dendritic cells, and NK cells. Its ligands, PD-L1 and PD-L2, are highly expressed on the surface of tumor cells. In the TME, tumor-infiltrating CD8+ T cells significantly influence the immune response. Activation of the TCR signaling pathway, leads T cells to increase the expression of immune checkpoints, sending a “negative feedback” that acts as an “immune brake” to reduce T-cell activation, thus allowing tumor cells to escape immune surveillance.^84,85 Intrinsic genetic aberrations and the dysregulation of signaling pathways in malignant cells usually drive PD-L1 expression. Studies have shown that copy number changes in the 9P24.1/PD-L1/PD-L2 gene fragment in PCNSL lead to increased expression of the PD-1 ligand PD-L1/PD-L2, which provides a basis for tumor immune escape and the application of PD-1 inhibitors.⁸⁶ Furthermore, inhibitors of PD-1 and CTLA-4 enhance the antitumor response of T cells and have been found to produce long-lasting antitumor activity in animal models of mouse intracranial tumors and in human clinical trials.¹⁴

The use of anti-PD-1 and anti-PD-L1 antibodies in clinical trials for solid tumors has yielded good clinical results. PD-1/PD-L1 inhibitors have also demonstrated effective biological effects on CNSL. Nivolumab, a PD-1 inhibitor, interacts with PD-1 to inhibit the immunosuppressive effect, thereby reactivating T cells’ ability to kill tumor cells. A case report assessed nivolumab's effectiveness in treating r/r PCNSL and primary testicular lymphoma (PTL). The report documented nivolumab treatment (3 mg/kg IV every 2 weeks) in four patients with r/r PCNSL and one patient with PTL, achieving complete remission (CR) in 4 patients and partial remission (PR) in 1 patient, with PFS was 14–17 months.⁴⁸ Currently, clinical studies use nivolumab for good response rates in r/r PCNSL.^48,49,87

PD-1 inhibitors can prevent apoptosis and exert an antitumor effect. Increased expression of PD-1 and PD-L1 in PCNSL provides a theoretical basis for its treatment and has shown effectiveness in r/r PCNSL, maintaining and prolonging disease remission. However, the evidence remains limited to a small number of cases, necessitating more data to determine its efficacy in PCNSL.

CAR-T Cell Therapy

Numerous clinical studies have shown that CAR-T cells can be successfully used to treat diseases such as B cell leukemia and lymphoma. Because normal CNS tissues lack CD19 expression, and almost all CNSL cells express CD19,^88–90 CD19-directed CAR-T therapy is utilized in CNSL to bind and recognize CD19, activate T cells, destroy malignant cells expressing CD19, and thereby exert antitumor effect.^91–93 However, the application of CAR-T cells in PCNSL can induce severe side effects, especially immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS).⁹⁴ Consequently, current studies on the use of CAR-T cells in PCNSL are relatively limited and focus primarily on secondary CNSL. In a study of CAR-T cells for SCNSL treatment, the cells showed activity in the CNS, and no patient experienced neurotoxicity greater than grade 1 in 8 patients.⁵¹ Furthermore, preclinical studies have shown that intracranial injection of CD19-directed CAR-T cells can mediate degeneration and control growth.^95,96 However, for the application of CAR-T cells to PCNSL, some limited data presented feasibility. A 67-year-old patient with PCNSL underwent therapy with CAR-T cells targeting CD19 and CD70. The results indicated that this dual-target approach was effective; the patient did not develop CRS or ICANS and achieved disease-free survival.⁵⁰ Wu et al administered sequential CD19/22 CAR-T cells infusion post-ASCT to 13 patients with CNSL, which included 4 cases of PCNSL and 9 cases of SCNSL. The findings demonstrated an overall remission rate of 81.81% and a CR rate of 54.5%, with a median duration of 14.03 months.⁵³ Another study confirmed that CAR-T cell therapy for CNSL is safe and reliable, although the remission duration was relatively short.⁵² It was previously assumed that CD19 was predominantly expressed in malignant B cells. However, subsequent research revealed that CD19 is also present in parietal cells of the blood-brain barrier, meaning that CD19-directed CAR-T cells target both tumor and parietal cells. This targeting results in damage to the parietal cells, potentially leading to severe neurotoxicity caused from CAR-T cell therapy.⁹⁷ Consequently, the development of a new generation of CAR-T cells aims to enhance their capability to differentiate between specific combinations of target antigens, thereby mitigating neurotoxicity.

CAR-T cell therapy is a novel approach to treating CNSL, offering new prospects for management. Currently, data on the application of CAR-T cells in CNSL are relatively limited, and their efficacy needs further evaluation. Moreover, serious adverse effects, including ICANS and CRS, may occur with CAR-T treatment. Therefore, it is crucial to focus on these side effects when implementing CAR-T cell therapy. Future research should aim to minimize treatment-related side effects of CAR-T cells.

PI3 K/mTOR Inhibitors

The phosphoinositide 3-kinase (PI3 K) /protein kinase B (AKT) /mammalian target of rapamycin(mTOR) pathway regulates protein synthesis by integrating growth factors, hormones, and nutrients to regulate cell growth and proliferation.⁹⁸ Preclinical and clinical data have shown that PI3 K/mTOR inhibitors exhibit antitumor activity in lymphoma cells and can be used alone or in combination with chemotherapy in r/r mantle cell lymphoma.^99,100 Moreover, AKT activates mTOR to regulate critical factors and promote cell proliferation. The mTOR kinase comprises mTORC1 and mTORC2. An activated mTORC1 continues to activate downstream targets S6 and 4E-BP1, which regulate cell growth and proliferation, while mTORC2 is activated by pathways other than PI3 K/AKT. Upon activation, it regulates upstream AKT signaling. Inhibitors can block the mTOR signaling pathway and inhibit the growth of lymphoma cells.¹⁰¹

Sirolimus is an immunosuppressant of mTOR. In a prospective study using sirolimus to treat r/r PCNSL, the results showed remission in about half of the patients, but the median PFS was very short, at only 2.1 months, and the side effects were large, reaching 13% of deaths due to complications from the drug.⁵⁶ The pan-PI3k inhibitor buparlisib did not show significant activity in CNSL and its drug concentration in the CNS was low, thus buparlisib monotherapy may not be active in CNSL.¹⁰²

The remission rate of PI3 K/mTOR inhibitors for PCNSL is not bad, but the duration of remission in patients is short and the drug side effects are large, which limits its application in PCNSL.

Immunotherapy in Combination

Although some drugs alone are effective for lymphoma, the combination of drugs with different mechanisms of action can enhance their efficacy. Additionally, certain drugs are susceptible to drug resistance, and pairing two drugs can help circumvent this issue (Table 3). In clinical studies, the R2 regimen, which includes lenalidomide combined with a CD20 monoclonal antibody, has demonstrated substantial efficacy in r/r PCNSL.^45,59 Lenalidomide with rituximab boosts the ADCC effect by augmenting FC receptor signaling, thereby stimulating NK cells and effectively decreasing the likelihood of rituximab resistance.^81,103 It also upregulates c-Jun N-terminal protein kinase phosphorylation and activates the mitochondria-derived apoptotic pathway, enhancing rituximab's ability to induce apoptosis.¹⁰⁴ Consequently, using lenalidomide with rituximab in PCNSL can synergistically diminish the tumor burden and counteract resistance to rituximab alone.¹⁰³ Furthermore, lenalidomide shows synergistic effects with BTK inhibitors. The binding substrate for lenalidomide in DLBCL cells is IRF4. When combined with ibrutinib for treating DLBCL, it can synergistically reduce IRF4 levels, alleviate the suppression of the IFN signaling pathway, and promote apoptosis of tumor cells, thereby achieving an effect where the sum is greater than the parts.⁷⁸ Furthermore, lenalidomide downregulates PD-L1 expression on the surface of lymphoma which may provide future prospects for combination therapy with lenalidomide and PD-1 inhibitors.¹⁰⁵ mTOR inhibitors combined with BTK inhibitors have synergistic effects against lymphoma,³⁷ suggesting that BTK inhibitors combined with mTOR inhibitors may be an effective combination therapy for PCNSL.

Table 3.

Mechanism and Efficacy of Combination Therapy of Immunotherapy.

Drug combination	The mechanism of action of drugs	Efficacy
Lenalidomide + rituximab	FC receptor signaling pathway↑→ADCC effect↑	Rituximab induction capacity↑
	FC receptor signaling pathway↑→ADCC effect↑	Rituximab resistance↓
	C-Jun N-terminal protein kinase Phosphorylation↑→mitochondria-derived apoptotic pathway↑	Rituximab induction capacity↑
		Rituximab resistance↓
Lenalidomide + ibrutinib	Synergistic downregulation of IRF4→IFN signaling pathway↑	Apoptosis of tumor cells↑
Lenalidomide + PD-1 inhibitor	Synergistic downregulation of PD-L1	Increased efficacy of PD-1 inhibitors
mTOR inhibitor + BTK inhibitor	Synergistic inhibition of mTOR	Synergistic induction CD79B-mutant PCNSL cell death

ADCC, antibody-dependent cell-mediated; IRF4, interferon regulatory factor 4; IFN, interferon.

Others

The B cell chemokines CXCL12 and CXCL13 are significantly expressed in CNSL but not in the normal brain. They mediate the chemotaxis of CNSL cells and promote tumor cells growth. Moreover, elevated CXCL13 levels in CSF are associated with poor prognosis. Therefore, targeting CXCL12 and CXCL13 may inhibit their tumor growth-promoting and chemotactic effects.^106,107 Recent data have also indicated that pharmacological antagonists of the CXCR4 receptor may effectively influence tumor cell growth.^108,109 The PCNSL in the immune microenvironment was compared with that in normal brain tissue by single-gene sequencing, macrophages were significantly downregulated in both gene expression and immune function in PCNSL. Therefore, future studies on the upregulation of gene expression and immune function in macrophages may provide new potential targets for the treatment of PCNSL.¹¹⁰

For immunotherapy and targeted therapy of PCNSL, in addition to some meaningful clinical trials, there are more clinical trials of new drugs and new combination regiments in progress. (Table 4).

Table 4.

Ongoing Randomized Clinical Trials on Therapy Targeting PCNSL.

Agents	Clinical trials	Phase	Estimated Enrollment	Conditions
Ibrutinib ± HD-MTX	NCT02315326	I, II	109	PCNSL, r/r PCNSL, r/r SCNSL
Rituximab, MTX ± lenalidomide	NCT04481815	II	240	PCNSL
Maintenance lenalidomide versus procarbazine following induction therapy with MTX plus rituximab and procarbazine	NCT03495960	II	208	PCNSL
Acalabrutinib	NCT04906902	I, II	49	r/r PCNSL
Tirabrutinib	NCT04947319	II	44	r/r PCNSL
Paxalisib	NCT04906096	II	25	r/r PCNSL
Tisagenlecleucel	NCT04134117	I	6	PCNSL, r/r PCNSL
Axicabtagene ciloleucel	NCT04608487	I	18	r/r PCNSL
Lisocabtagene maraleucel	NCT03484702	II	112	r/r PCNSL

Conclusions

PCNSL is characterized by high malignancy, rapid progression, and poor prognosis. The prognosis of this disease has significantly improved with the application of HD-MTX. However, conventional chemotherapy has highly toxic side effects, low tolerability, and a high relapse rate, prompting intensive immunotherapy and targeted therapy research. PCNSL has a unique TME that interacts with the tumor and regulates its development and progression. New immunotherapies and targeted therapies such as CD20 monoclonal antibodies, immunomodulators, immune checkpoint inhibitors, CAR-T cells, BTK inhibitors, and mTOR inhibitors can exert antitumor effects by targeting tumor cells and modulating the TME. These therapies have promising applications in preclinical and clinical practice, offering new hope and possibilities for the treatment of PCNSL. The combination of these drugs can also synergize to inhibit tumor growth and provide additional possibilities for enhancing the efficacy of PCNSL treatment. Future therapies for PCNSL should continue to be explored.

Footnotes

Acknowledgments

We thank all colleagues for their suggestions on this review. We thank CINEMA 4D for helping us in our drawing process.

Author Contributions

All authors conceived and drafted the manuscript, drew the figures, and discussed the concepts of the manuscript. Xiaoyin Liu and Jing Chen provided valuable discussion and funding. Lin Zhong, Anqing Lu, Xiyue Lu, Xiaoyin Liu, Lujia Cao, Shihong Zhu, SiJun Diao, Xu Cheng, Hongwei Wu, and Jing Chen provided valuable discussion and revised the manuscript. All authors have read and approved the final manuscript.

Declaration of Conﬂicting Interests

The authors declared no potential conﬂicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics Statement

This article is a review article and it does not involve related animal and patient studies.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82401629), the China Postdoctoral Science Foundation (Grant No. 2024T170601, 2024M762228 and GZC20231811), the Sichuan Science and Technology Program (Grant No. 2023YFS0164), and the Natural Science Foundation of Sichuan Province (Grant No. 2024NSFSC1646).

ORCID iD

Xiaoyin Liu

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Molecular Mechanisms and Therapeutic Prospects of Immunotherapy and Targeted Therapy in Primary Central Nervous System Lymphoma

Abstract

Keywords

Introduction

Search Strategy

Microenvironment of the Brain

Unique Microenvironment of PCNSL

Immunotherapy in PCNSL

CD20 Monoclonal Antibody

BTK Inhibitors

Immunomodulatory Drugs

Immune Checkpoint Inhibitors

CAR-T Cell Therapy

PI3 K/mTOR Inhibitors

Immunotherapy in Combination

Others

Conclusions

Footnotes

Acknowledgments

Author Contributions

Declaration of Conﬂicting Interests

Ethics Statement

Funding

ORCID iD

References