Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential
Abstract
:1. Introduction
2. Therapeutic Strategies
2.1. Immune Checkpoint Inhibitors
2.2. Small Molecule Inhibitors
2.3. PI3K Inhibitors
2.4. Targeting the NF-κB Pathway
2.5. CD47 Inhibitors
2.6. Neddylation Inhibitors
2.7. PD-1 Inhibitors
2.8. CTL-4 Inhibitors
2.9. T Cell and NK-Cell Therapy
2.10. Macrophages
2.11. Summary the Proposed Therapies
3. Innovative Combination Therapies for Hematologic Malignancies: Enhancing Treatment Efficacy and Overcoming Resistance
3.1. PI3K Inhibitors in Combination Therapies
3.2. Immunological Checkpoint Inhibitors in Combination Therapies
3.3. NF-κB Inhibitors in Combination Therapies
3.4. Neddylation Inhibitors in Combination Therapies
3.5. Summary of Combination Therapies for Hematologic Malignancies
4. Other Innovative Combination Therapies for Hematologic Malignancies
Summary Table
5. Potentially Toxic Therapies
6. Discussion
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug | Mechanism of Action/Target/Type of Molecule | Type of Malignancy | Approval Status | Combination Therapies | Adverse Effects |
---|---|---|---|---|---|
MBG453 | TIM-3 inhibitor/Antibody | Lymphomas, advanced solid tumors | Clinical Trials II | Investigated with other immune checkpoint inhibitors | Fatigue, nausea |
Sym023 | TIM-3 inhibitor/Monoclonal antibody | Advanced solid tumors, lymphomas | Clinical Trials I/II | Research ongoing for combinations | Fatigue, infusion reactions |
LY3321367 | TIM-3 inhibitor/Antibody | Solid tumors, hematologic malignancies | Clinical Trials I/II | Being studied with other therapies | Under investigation |
LY3415244 | Anti-TIM-3 antibody | Solid tumors and hematologic malignancies | Clinical Trials I/II | Combination immunotherapy | Under investigation |
TSR-022 | Anti-TIM-3 antibody | Solid tumors and lymphomas | Clinical Trials I/II | Being tested with other checkpoint inhibitors | Under investigation |
Lomvastomig: RO7121661 | TIM-3 inhibitor/Bispecific antibody | Advanced solid tumors and lymphomas | Clinical Trials I/II | Research ongoing for combinations | Under investigation |
TSR-042 | Anti-PD-1 and TIM-3 antibody | Various cancers | Clinical Trials II | Being studied with other immunotherapies | Fatigue, immune-related adverse events |
Agent Name | Mechanism of Action | Hematological Malignancies | Clinical Development Phase |
---|---|---|---|
Tiragolumab | Anti-TIGIT monoclonal antibody | NHL, MM | Phase II |
Vibostolimab | Anti-TIGIT monoclonal antibody | HL | Phase II |
Ociperlimab | Anti-TIGIT monoclonal antibody | AML | Phase I/II |
AGEN1777 | Bispecific antibody targeting TIGIT and PD-1 | MM, NHL | Phase I/II |
COM902 | Anti-TIGIT monoclonal antibody | MM | Phase I |
AB154 | Anti-TIGIT monoclonal antibody | CLL | Phase I |
Name of Molecule | Mechanism of Action | Type of Hematologic Malignancy | Approval Status | Clinical Trial Phase | Adverse Effects |
---|---|---|---|---|---|
Idelalisib (Zydelig) | Inhibits PI3Kδ, reducing cell proliferation and survival signals | CLL, FL, SLL | FDA Approved | N/A | Diarrhea, liver toxicity |
Copanlisib (Aliqopa) | Inhibits PI3Kα and PI3Kδ, affecting cell growth and survival | FL | FDA Approved | N/A | Hyperglycemia, hypertension |
Duvelisib (Copiktra) | Inhibits PI3Kδ and PI3Kγ, reducing cytokine synthesis and promoting apoptosis | CLL, SLL | FDA Approved | N/A | Diarrhea, colitis |
TGR-1202 (Umbralisib) | Inhibits PI3Kδ and casein kinase-1ε (CK1ε), affecting cell adhesion and migration | CLL, MZL, FL | FDA Approved | N/A | Diarrhea, nausea |
Zandelisib (ME-401) | Inhibits PI3Kδ, affecting cell proliferation and survival signals | FL, CLL, SLL, MZL, DLBCL | Clinical Trials | II/III | Diarrhea, liver toxicity |
Linperlisib | Inhibits PI3Kδ, reducing cell proliferation and survival signals | FL | Clinical Trials | I/II | Fatigue, nausea |
TQB3525 | Inhibits PI3Kα and PI3Kδ, affecting cell growth and survival | CLL, SLL | Clinical Trials | I/II | Under investigation |
Acalisib | Inhibits PI3Kδ, reducing cell proliferation and survival signals | FL, DLBCL, MZL, MCL | Clinical Trials | I | Under investigation |
SHC014748M | Inhibits PI3Kδ, reducing cell proliferation and survival signals | CLL | Preclinical | N/A | Under investigation |
Venetoclax | Inhibits BCL-2, promoting apoptosis in cancer cells | CLL, AML | FDA Approved | N/A | Neutropenia, infections |
Selinexor | Inhibits XPO1, blocking nuclear export and leading to apoptosis | MM, DLBCL | FDA Approved | N/A | Nausea, fatigue |
Bortezomib | Inhibits proteasome activity, leading to the accumulation of pro-apoptotic proteins and triggering apoptosis | MM | FDA Approved | N/A | Peripheral neuropathy, fatigue |
Melphalan | Binds at the N7 position of guanine, inducing inter-strand cross-links in DNA | MM | FDA Approved | N/A | Bone marrow suppression |
P5091 | Inhibits USP7, blocking HDM2 and p21 signaling pathways | MM | Clinical Trials | I/II | Well tolerated in studies |
Name of Molecule | Target | Type of Malignancy | Approval Status | Mechanism of Action | Combination Therapies | Adverse Effects |
---|---|---|---|---|---|---|
Idelalisib (Zydelig) | Inhibitor of PI3K-Delta | CLL, FL, SLL | FDA Approved | Induces caspase-dependent apoptosis | Being studied with anti-CD20 antibodies | Diarrhea, colitis, liver toxicity |
Copanlisib (Aliqopa) | Inhibitor of PI3K-alpha and PI3K delta | FL | FDA Approved | Inhibits PI3K signaling, affecting cell proliferation and survival | Used with rituximab | Hyperglycemia, hypertension |
Duvelisib (Copiktra) | Inhibitor of PI3K-delta and PI3K-gamma | CLL and SLL | FDA Approved | Reduces cytokine synthesis, direct cytotoxicity to leukemic cells | Investigated with BTK inhibitors | Diarrhea, colitis, pneumonitis |
TGR-1202 (Umbralisib) | Dual PI3Kδ and CK1ε inhibitor | CLL, MZL, FL | FDA Approved | Inhibits PI3Kδ and CK1ε, reduces tumor cell adhesion and migration | Combined with BTK inhibitors | Diarrhea, nausea, fatigue |
Zandelisib (ME-401) | Inhibitor of PI3K-Delta | FL, CLL, SLL, MZL, DLBCL | Phase II/III Clinical | Inhibits PI3K signaling, affecting cell proliferation and survival | Being tested with rituximab | Diarrhea, liver toxicity |
Linperlisib | Inhibitor of PI3K-Delta | FL | Phase I/II Clinical | Inhibits PI3K signaling pathways | Combined with other chemotherapies | Fatigue, nausea |
TQB3525 | Inhibitor of PI3K-alpha and PI3K delta | CLL, SLL | Phase I/II Clinical | Targets PI3K signaling, affects cell survival | Research ongoing for combinations | Under investigation |
Acalisib | Inhibitor of PI3K-Delta | FL, DLBCL, MZL, MCL | Phase I Clinical | Inhibits PI3Kδ, impacting cell survival | Studied with chemotherapy agents | Under investigation |
SHC014748M | Inhibitor of PI3K-Delta | CLL | Preclinical | Targets PI3K signaling pathways | Potential for combination therapy | Under investigation |
Name of Molecule | Mechanism of Action | Type of Hematologic Malignancy | Type of Molecule | Approval Status | Combination Therapies | Adverse Effects |
---|---|---|---|---|---|---|
Curcumin | Inhibits NF-κB activation by suppressing various upstream signaling pathways | MM | Diarylheptanoid (curcuminoids group) | Preclinical | Research ongoing for combinations | Generally well tolerated |
Bay 11-7082 | Inhibits NF-κB activation by targeting the IκB kinase complex, preventing phosphorylation of IκBα | MM, L | IκB Kinase (IKK) inhibitor | Preclinical | Investigated with other inhibitors | Under investigation |
Parthenolide | Inhibits NF-κB activation by targeting the IκB kinase complex, preventing phosphorylation of IκBα | ALL, L | Germacranolide | Preclinical | Investigated with other NF-κB inhibitors | Cytotoxicity at high doses |
IKK Inhibitor MLN120B | Targets IKK complex, preventing phosphorylation of IκBα | VL and L | Small molecule inhibitor | Preclinical | Investigated with chemotherapies | Under investigation |
Resveratrol | Inhibits NF-κB activation by suppressing phosphorylation and degradation of IκBα, preventing NF-κB translocation | VL and L | Polyphenolic phytoalexin (Stilbene class) | Clinical Trials I/II | Combined with chemotherapies | Mild gastrointestinal symptoms |
Name of Molecule | Target | Type of Malignancy | Type of Molecule | Approval Status | Combination Therapies | Adverse Effects |
---|---|---|---|---|---|---|
Hu5F9-G4 | Selectively binds to CD47 expressed on tumor cells and blocks the interaction with SIRPa | AML, MM, LBCL, and some solid tumors | Peptide (monoclonal antibody) | Clinical Trials I/II | Investigated with other chemotherapies | Anemia, fatigue |
SIRPαFc (TTI-621) | Binds to CD47 on tumor cells, preventing inhibitory signals to macrophages, and engages FcγR to enhance phagocytosis | Relapsed/refractory hematologic malignancies and solid tumors | Peptide | Clinical Trials I/II | Combined with other immune checkpoint inhibitors | Thrombocytopenia, anemia |
CC-90002 | Anti-CD47 antibody that inhibits CD47-SIRPα interaction, enabling macrophage-mediated killing of tumor cells | Relapsed/refractory hematologic malignancies and solid tumors | Peptide (antibody) | Clinical Trials I/II | Investigated with other mAbs | Cytokine release syndrome |
ALX148 | Enhances macrophage phagocytosis of tumor cells and inhibits binding of wild-type SIRPα | Non-Hodgkin Lymphoma and solid tumors | Peptide (antibody) | Clinical Trials I/II | Combined with rituximab, pembrolizumab | Infusion reactions, anemia |
Name of Molecule | Mechanism of Action | Type of Hematologic Malignancy | Type of Molecule | Approval Status | Combination Therapies | Adverse Effects |
---|---|---|---|---|---|---|
Pevonedistat (MLN4924) | Inhibits NEDD8-activating enzyme (NAE), disrupting neddylation, inducing apoptosis, senescence, and autophagy via p53 pathway activation | AML, MM, MDS | NEDD8-activating enzyme inhibitor | Clinical Trials II/III | Investigated with chemotherapies and immunotherapies | Nausea, fatigue, and hematologic toxicity |
TAS4464 | Selectively inhibits NAE, leading to cullin neddylation inhibition and accumulation of CRL substrates, inducing antiproliferative activity | AML, MM | NEDD8-activating enzyme inhibitor | Clinical Trials I/II | Investigated with molecular and hormonal therapies | Under investigation |
MLN4924 | Inhibits NAE, leading to the activation of the p53 signaling pathway and subsequent anti-leukemia effects | AML, MM | NEDD8-activating enzyme inhibitor | Clinical Trials II/III | Investigated with molecular, immunotherapy-based therapies | Nausea, fatigue, hematologic toxicity |
TAS4464 | Highly potent NAE inhibitor, inducing cullin neddylation inhibition and CRL substrate accumulation, leading to widespread antiproliferative activity | AML, MM | NEDD8-activating enzyme inhibitor | Clinical Trials I/II | Combined with molecular therapies, CD47 receptor blockade | Under investigation |
Name of Inhibitor | Clinical Trial Phase | Mechanism of Action | Type of Hematologic Malignancy | FDA Status | Combination Therapies | Adverse Effects |
---|---|---|---|---|---|---|
Nivolumab (Opdivo) | III/IV | Inhibits PD-1, preventing binding with PD-L1/PD-L2 and restoring T-cell activity | HL | Approved | Chemotherapy, targeted therapy, other immunotherapies | Fatigue, rash, diarrhea, hepatitis |
Pembrolizumab (Keytruda) | III/IV | Inhibits PD-1, preventing binding with PD-L1/PD-L2 and restoring T-cell activity | HL, PMBCL | Approved | Chemotherapy, targeted therapy, other immunotherapies | Fatigue, pruritus, rash, pneumonitis |
Cemiplimab (Libtayo) | III/IV | Inhibits PD-1, preventing binding with PD-L1/PD-L2 and restoring T-cell activity | HL | Clinical Trials | Chemotherapy, targeted therapy | Fatigue, rash, musculoskeletal pain |
Sintilimab | III/IV | Inhibits PD-1, preventing binding with PD-L1/PD-L2 and restoring T-cell activity | HL | Approved (China) | Chemotherapy, targeted therapy, other immunotherapies | Pyrexia, hypothyroidism, pneumonia |
Toripalimab | III/IV | Inhibits PD-1, preventing binding with PD-L1/PD-L2 and restoring T-cell activity | HL | Approved (China) | Chemotherapy, targeted therapy, other immunotherapies | Fatigue, fever, hypothyroidism |
Camrelizumab | III/IV | Inhibits PD-1, preventing binding with PD-L1/PD-L2 and restoring T-cell activity | HL | Approved (China) | Chemotherapy, targeted therapy, other immunotherapies | Rash, pruritus, arthralgia |
Target | Applications | Mechanism of Action | Clinical Impact |
---|---|---|---|
Rituximab (Rituxan) CD20 antigen on B cells [64]. | Rituximab is primarily used in the treatment of BNHL, including DLBCL and FL, as well as in CLL. | Rituximab binds to the CD20 antigen on B cells, leading to cell death through complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and direct induction of apoptosis. | The introduction of Rituximab has significantly improved survival rates in B-cell malignancies. It is often used in combination with chemotherapy (e.g., the R-CHOP regimen) and as maintenance therapy to prevent relapse. |
Daratumumab (Darzalex) CD38 antigen on plasma cells [65]. | Daratumumab is widely used in the treatment of MM, both as a monotherapy and in combination with other agents like lenalidomide, bortezomib, and dexamethasone. | Daratumumab targets CD38, leading to cell death through CDC, ADCC, antibody-dependent cellular phagocytosis (ADCP), and apoptosis. | Daratumumab has transformed the treatment landscape for MM, offering significant improvements in progression-free survival and overall survival, particularly in relapsed and refractory settings. |
Brentuximab Vedotin (Adcetris) CD30 antigen on Reed-Sternberg cells and some TCL [66]. | Brentuximab Vedotin is used in the treatment of HL and certain types of TCL, including ALCL. | This antibody-drug conjugate (ADC) consists of a CD30-directed monoclonal antibody linked to the cytotoxic agent monomethyl auristatin E (MMAE). Upon binding to CD30, the conjugate is internalized, and MMAE is released, leading to cell cycle arrest and apoptosis. | Brentuximab Vedotin has shown high efficacy in relapsed and refractory HL and ALCL, providing an important treatment option, especially for patients who have failed conventional chemotherapy. |
Inotuzumab Ozogamicin (Besponsa) CD22 antigen on B cells [67]. | Inotuzumab Ozogamicin is used in the treatment of relapsed or refractory B-cell ALL. | This ADC targets CD22, delivering the cytotoxic antibiotic calicheamicin directly to the cancer cells, leading to DNA damage and cell death. | Inotuzumab Ozogamicin has improved outcomes in relapsed/refractory ALL, offering a targeted therapy option with high response rates in a difficult-to-treat patient population. |
Elotuzumab (Empliciti) SLAMF7 (signaling lymphocytic activation molecule family member 7) on myeloma cells and natural killer (NK) cells [68]. | Elotuzumab is used in combination with lenalidomide and dexamethasone for the treatment of MM, particularly in relapsed/refractory cases. | Elotuzumab enhances NK cell-mediated ADCC against SLAMF7-expressing myeloma cells, while also activating NK cells to attack the cancer cells. | Elotuzumab has been shown to improve progression-free survival in patients with MM, especially when used in combination therapy. |
Alemtuzumab (Campath) CD52 antigen on B and T cells [69]. | Alemtuzumab is used in the treatment of CLL and, in some cases, T-PL. | Alemtuzumab targets CD52, leading to cell death through CDC and ADCC. | Alemtuzumab has been effective in CLL, particularly in patients with 17p deletion who are typically resistant to other therapies. However, its use is limited due to significant immunosuppression and infection risks. |
Name of Inhibitor | Mechanism of Action | Type of Hematologic Malignancy | Approval Status | Combination Therapies | Clinical Trial Phase | Adverse Effects |
---|---|---|---|---|---|---|
Ipilimumab (Yervoy) | Inhibits CTLA-4, leading to enhanced T cell activation and proliferation | RHL | FDA Approved | Combined with nivolumab (PD-1 inhibitor) | III/IV | Fatigue, diarrhea, rash, colitis |
Tremelimumab | Inhibits CTLA-4, leading to enhanced T cell activation and proliferation | RHL | Clinical Trials | Combined with durvalumab (PD-L1 inhibitor) | III | Fatigue, nausea, rash, colitis |
AGEN1884 | Inhibits CTLA-4, enhancing T cell activation and proliferation | VHM | Clinical Trials | Combined with other immunotherapies | I/II | Under investigation |
RELA-067 | Inhibits CTLA-4, leading to enhanced T cell activation and proliferation | VHM | Clinical Trials | Combined with other immunotherapies | I/II | Under investigation |
ONC-392 | Inhibits CTLA-4, reducing regulatory T cell suppression and enhancing effector T cell function | VHM | Clinical Trials | Combined with PD-1/PD-L1 inhibitors | I/II | Under investigation |
XmAb20717 | Bispecific antibody targeting CTLA-4 and PD-1, enhancing T cell activation | VHM | Clinical Trials | Monotherapy and combination with other checkpoint inhibitors | I/II | Under investigation |
Approach | Description | Therapeutic Application | Status |
---|---|---|---|
NK Cells + Immune Checkpoint Blockade | Combination of NK cells with checkpoint inhibitors to enhance immune response | VC | Clinical Trials |
CAR-NK Cell Therapy | NK cells engineered to express chimeric antigen receptors for targeted cancer cell elimination | HM, ST | Clinical Trials |
CAR-T Cell Therapy | T cells engineered to express chimeric antigen receptors for targeted cancer cell elimination | HM, ST | FDA Approved, Clinical Trials |
Artificial Adjuvant Vector Cells | Artificial cells designed to enhance NK and T cell activation and targeting | VC | Preclinical/Clinical Trials |
NK Cells + Monoclonal Antibodies | NK cells used in conjunction with monoclonal antibodies to target specific cancer cells | HM | Clinical Trials |
TCR-Engineered T Cell Therapy | T cells engineered to express specific T cell receptors for precise targeting of cancer antigens | HM, ST | Clinical Trials |
NK Cells + Cytokine Therapy | Combination of NK cells with cytokines to boost immune response against cancer cells | VC | Preclinical/Clinical Trials |
Bispecific T-Cell Engagers (BiTEs) | Antibodies that simultaneously bind to T cells and cancer cells, bringing them into proximity | HM, ST | FDA Approved, Clinical Trials |
NK Cell-Derived Exosomes | Exosomes derived from NK cells used for delivering therapeutic molecules | VC | Preclinical Trials |
Trispecific Killer Engager (TriKE) | Molecules that engage NK cells with cancer cells and provide a co-stimulatory signal | HM | Preclinical/Clinical Trials |
Dual-Affinity Re-Targeting (DART) molecules | Antibodies designed to bind two different antigens, enhancing immune cell targeting | VC | Preclinical/Clinical Trials |
Macrophage Function | Action | Effect |
---|---|---|
Cytokines and Chemokines | Cytokines such as interferons (IFNs), tumor necrosis factor alpha (TNF-α), interleukins (e.g., IL-1, IL-6, IL-12), and chemokines released by other immune cells or produced by macrophages themselves can activate macrophages. | These small molecules bind to specific receptors on macrophages, initiating signaling pathways that induce their activation. |
Opsonization | Opsonins, such as antibodies and complement proteins, coat pathogens and enhance their recognition and phagocytosis by macrophages. | Engagement of opsonin receptors on macrophages triggers signaling events that lead to their activation and phagocytic activity. |
Phagocytic Receptors | Macrophages express various phagocytic receptors, including Fc receptors and complement receptors, which recognize opsonized pathogens and facilitate their internalization. | Successful binding of these receptors activates downstream signaling pathways that promote phagocytosis and microbial killing. |
Inflammatory Mediators | Inflammatory mediators such as prostaglandins, leukotrienes, and reactive oxygen species (ROS) released during inflammation can activate macrophages. | These molecules contribute to the inflammatory response and induce macrophage activation, promoting enhanced anti-tumor activity in hematologic malignancies. |
Toll-like receptor (TLR) agonists | TLRs are key molecular sensors that recognize the presence of pathogens and other danger signals. | Stimulation of TLRs on macrophages can lead to their activation and increased ability to eliminate hematologic cancer cells. |
Interferons | When used in combination therapy, they can activate macrophages, stimulate the production of chemokines and pro-inflammatory cytokines, and increase the expression of MHC molecules on cancer cells. | This facilitates their recognition by the immune system, resulting in the activation of downstream signaling, deciding the fate of hematologic cancer cells. |
CAR-M | Macrophages are engineered to express receptors on their surface, facilitating the recognition of surface antigens either with antibodies or specific ligands present on target cells. | CAR-Ms can phagocytose tumors directly after identifying specific antigens on hematologic cancer cells. Additionally, active CAR-Ms may secrete inflammatory molecules such as IFN-γ, IL-12, and TNF-α to encourage M1 polarization and activate antigen-presenting cells (APCs) in the tumor microenvironment (TME). |
Name of Therapy | Potential Benefits | Disadvantages |
---|---|---|
TIM-3 (T cell immunoglobulin and mucin domain 3) | Combined PD-1/PD-L1 with TIM-3/Gal-9 blockade could prevent CD8+ T-cell exhaustion in advanced AML [85]. PD-1 combined with TIM-3 blockades could stimulate potential anti-tumor T cell responses in melanoma [86]. In xenograft models, anti-TIM-3 IgG2a antibody could improve cytotoxic activities and eradicate AML leukemic stem cells [87]. | Lack of valid biomarkers which can predict successful treatment with this combination [88]. Combinations will have to be patient-tailored since they are likely to be more toxic than single agents and more expensive. Cells usually have functionally redundant pathways which could override and compensate for each other [89]. |
TIGIT | TIGIT suppresses both innate and adaptive immunity by a variety of mechanisms, such as initiating T/NK cell-intrinsic inhibition, producing immunosuppressive DCs, blocking CD226 signaling, boosting Treg immunosuppression, and encouraging Fap2-induced T/NK cell inhibition [90]. | There is currently no reliable biomarker for anti-TIGIT therapy. As a result, future studies should concentrate on identifying new biomarkers or targeting TIGIT using alternative strategies, such as CAR-T cells, antibody-drug conjugates, and bispecific antibodies [91]. |
Small molecule inhibitors | Easier cellular entry, oral effectiveness, and comparatively cost-efficient synthesis [8]. In vivo studies indicate that P5091 is well tolerated, inhibits malignant cell growth, and extends survival [23]. | Pulmonary toxicity in preclinical studies [19]. Studies on biochemical and cellular characterization of lead compounds, in addition to extensive PK, pharmacodynamics, and toxicology studies, are required [92]. |
PI3K inhibitors | Several inhibitors passed clinical trials and are approved by FDA. Demonstrated desired therapeutic effects on various cancers. Several inhibitor alternatives available in market [93]. | Adverse effects remain major concern for this therapy. On-target toxicities severely limit the development of PI3K inhibitors [93]. |
NFkB inhibitors | Inhibits NF-κB activation by sup-pressing phosphorylation and degradation of IκBα, preventing NF-κB translocation [47]. Inhibits NF-κB activation by targeting the IκB kinase complex and preventing phosphorylation of IκBα [94]. | Mild gastro-intestinal symptoms [47]. Cytotoxicity at high doses [94]. |
CD47 Inhibitors | This therapy aims to synergistically boost the immune system’s ability to target and eliminate cancer cells, while also overcoming resistance mechanisms that tumors may develop [52]. | These limitations include resistance mechanisms, toxicity, lack of predictive biomarkers, inadequate effectiveness as a monotherapy, and production difficulties [95]. |
Neddylation Inhibitors | Widespread antiproliferative activity in cancer cell lines and patient-derived tumor cells, making it a promising agent for hematologic tumors [57]. Currently under phase II/III clinical trials for anti-tumor treatment and shows good safety and tolerability, indicating its good development prospects [96]. | Drug resistance is a major challenge [96]. |
Combination Therapy | Components | Mechanism of Action | Potential Benefits | Clinical Status |
---|---|---|---|---|
PI3K Inhibitor + Proteasome Inhibitor | Idelalisib + Bortezomib | PI3K inhibitors impede signaling pathways regulating cell growth; proteasome inhibitors block protein degradation | Synergistic anti-cancer effects, reduced cell proliferation, enhanced apoptosis | Clinical Trials |
PI3K Inhibitor + Immunological Checkpoint Inhibitor | Idelalisib + TIM-3/TIGIT inhibitors | PI3K inhibitors reduce immunosuppression; checkpoint inhibitors enhance T cell activation | Enhanced immune response, suppressed tumor cell proliferation | Preclinical/Clinical Trials |
Immunological Checkpoint Inhibitor + Proteasome Inhibitor | PD-1/CTLA-4 inhibitors + Bortezomib | Checkpoint inhibitors boost immune response; proteasome inhibitors regulate apoptosis-controlling protein expression | Enhanced tumor cell apoptosis, boosted immune response | Clinical Trials |
NF-κB Inhibitor + TIGIT Inhibitor | NF-κB inhibitors + TIGIT inhibitors | NF-κB inhibitors regulate signaling pathways; TIGIT inhibitors reduce Treg-mediated immunosuppression | Reduced tumor cell proliferation, heightened immune response | Preclinical |
NF-κB Inhibitor + Monoclonal Antibody Therapy | NF-κB inhibitors + Monoclonal antibodies | NF-κB inhibitors block survival pathways; monoclonal antibodies target cancer cell receptors | Synergistic anti-tumor impact, enhanced immune-mediated tumor eradication | Preclinical/Clinical Trials |
Neddylation Inhibitor + Tumorigenesis Inhibitor | MLN4924 + Tumorigenesis inhibitors | Neddylation inhibitors block protein degradation; tumorigenesis inhibitors impede growth and proliferation processes | Enhanced tumor cell apoptosis, restrained tumor growth and metastasis | Preclinical |
Neddylation Inhibitor + Antigen Complex Therapy | MLN4924 + Antigen complex therapy | Neddylation inhibitors prevent protein degradation; antigen complex therapy elicits immune response | Increased tumor cell apoptosis, mounted immune response | Preclinical |
CAR-T Cell Therapy + Immunological Checkpoint Inhibitor | CAR-T cells + Pembrolizumab | CAR-T cells target and eliminate cancer cells; checkpoint inhibitors enhance CAR-T cell persistence and function | Augmented CAR-T cell efficacy, enhanced immune response | Clinical Trials |
CAR-T Cell Therapy + Radiotherapy | CAR-T cells + Radiotherapy | CAR-T cells target cancer cells; radiotherapy enhances tumor cell destruction | Improved anti-cancer immune response, enhanced tumor cell destruction | Clinical Trials |
CAR-T Cell Therapy + Immunomodulatory Drugs | CAR-T cells + Immunomodulatory drugs | CAR-T cells target tumor cells; immunomodulatory drugs boost T cell proliferation and persistence | Effective tumor eradication, enhanced cytokine production | Clinical Trials |
Signaling Cascade Inhibitors + Immune Checkpoint Inhibitors | Ibrutinib + Anti-PD-1/PD-L1 antibodies | Signaling inhibitors regulate growth pathways; checkpoint inhibitors boost immune response | Overcome resistance, enhanced anti-tumor immune response | Clinical Trials |
CD47 Inhibitor + CAR-T Therapy | Hu5F9-G4 + CAR-T cells | CD47 inhibitors increase phagocytosis of cancer cells; CAR-T cells target and eliminate cancer cells | Enhanced phagocytosis, robust immune response | Clinical Trials |
NF-κB Inhibitor + Hyperthermia Therapy | NF-κB inhibitors + Hyperthermia | NF-κB inhibitors block survival pathways; hyperthermia increases treatment sensitivity | Increased apoptosis, enhanced treatment efficacy | Preclinical |
Combination Therapy | Components | Mechanism of Action | Potential Benefits | Clinical Status |
---|---|---|---|---|
CAR-T Therapy + Oncolytic Virus Therapy | CAR-T cells + Oncolytic viruses | Enhanced CAR-T cell infiltration and activity, direct oncolytic effects | Increased CAR-T cell efficacy, enhanced immune response | Preclinical/ Clinical Trials |
Epigenetic Modifiers + Immunotherapy | Epigenetic drugs + CAR-T cells/checkpoint inhibitors | Improved tumor antigen expression, enhanced immune recognition and response | Improved immune response, enhanced tumor antigen presentation | Preclinical/ Clinical Trials |
Metabolic Inhibitors + Immune Checkpoint Inhibitors | Metabolic inhibitors + Checkpoint inhibitors | Disrupted cancer cell metabolism, reduced tumor growth, enhanced immune response | Enhanced antitumor response, reduced tumor growth | Preclinical/ Clinical Trials |
PARP Inhibitors + Immunotherapy | PARP inhibitors + CAR-T cells/checkpoint inhibitors | Increased DNA damage, improved immune recognition, and response | Enhanced tumor cell death, improved immune response | Preclinical/ Clinical Trials |
Autophagy Inhibitors + Chemotherapy | Autophagy inhibitors + Chemotherapy | Increased chemotherapy efficacy, reduced cancer cell survival | Enhanced chemotherapy effects, reduced tumor cell survival | Preclinical/ Clinical Trials |
Bcl-2 Inhibitors + Immunotherapy | Bcl-2 inhibitors + CAR-T cells/checkpoint inhibitors | Increased tumor cell apoptosis, enhanced immune response | Improved tumor cell death, enhanced immune response | Preclinical/ Clinical Trials |
Proteasome Inhibitors + Histone Deacetylase Inhibitors | Proteasome inhibitors + Histone deacetylase inhibitors | Synergistic induction of apoptosis, improved tumor cell death | Enhanced apoptosis, improved tumor cell death | Preclinical/ Clinical Trials |
Checkpoint Inhibitors + TLR Agonists | Checkpoint inhibitors + TLR agonists | Enhanced activation of innate and adaptive immune responses, improved antitumor activity | Improved immune response, enhanced tumor destruction | Preclinical/ Clinical Trials |
Angiogenesis Inhibitors + Immune Checkpoint Inhibitors | Angiogenesis inhibitors + Checkpoint inhibitors | Reduced tumor vascularization, enhanced immune response | Reduced tumor growth, improved immune cell infiltration | Preclinical/ Clinical Trials |
Anti-CD47 Therapy + Radiotherapy | Anti-CD47 antibodies + Radiotherapy | Enhanced phagocytosis, improved immune response, increased tumor cell death | Improved tumor clearance, enhanced immune response | Preclinical/ Clinical Trials |
Therapy | Target Disease | Combination | Reason for Failure |
---|---|---|---|
Orelabrutinib | BCM | - | Significant safety concerns |
Nemtabrutinib (formerly ARQ 531) | CLL and MCL | - | Efficacy and safety issues |
TTI-621 | Relapsed or RHM | - | Significant safety issues |
Hu8F4 | AML and CMML | - | Limited efficacy and significant toxicity |
Ivosidenib and Venetoclax with or without Azacitidine | IDH1-mutated HM | Combination of Ivosidenib and Venetoclax, sometimes with Azacitidine | Safety challenges and unmet therapeutic outcomes |
Afuresertib and Fulvestrant | HR+/HER2 BC (with implications for HM) | Combination of Afuresertib and Fulvestrant | Insufficient efficacy in Phase III trials |
Rilotumumab | GC and HM | - | Safety concerns and lack of efficacy in Phase III trials |
Bavituximab | NSCLC and HM | - | Lack of efficacy in Phase III trials |
Selinexor | MM and other HM | - | Significant toxicity and limited efficacy in later-stage trials |
Future Actions and Direction Lines for Combinational Therapies | |
---|---|
Targeted Combinations | As genomic profiling becomes more sophisticated, therapies will increasingly be tailored to the genetic and molecular characteristics of individual patients’ tumors. This approach will enable the selection of drug combinations that target specific mutations, pathways, or microenvironmental factors driving the malignancy [142,143]. |
Predictive Biomarkers | The identification and validation of biomarkers that predict response to specific drug combinations will play a crucial role in personalizing therapy. For example, using biomarkers to guide the use of immunotherapy combinations with targeted therapies could optimize treatment efficacy and minimize toxicity [144]. |
Immunotherapy Combinations | CAR-T cells with immune checkpoint inhibitors: CAR-T therapy has shown remarkable success in some hematologic malignancies, but resistance and relapse remain challenges. Combining CAR-T cells with immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 or anti-CTLA-4) could enhance the persistence and efficacy of CAR-T cells by overcoming the immunosuppressive tumor microenvironment [142,143]. |
Bispecific Antibodies and Cytokines | The use of bispecific antibodies that target both the cancer cells and immune cells, combined with cytokine therapies to boost the immune response, is a promising strategy. These combinations aim to enhance the immune system’s ability to recognize and eliminate cancer cells more effectively [145]. |
Stromal and Immune Modulators | The tumor microenvironment, including stromal cells, immune cells, and the extracellular matrix, plays a critical role in the progression and resistance of hematologic malignancies. Combinational therapies that target both the cancer cells and their supportive microenvironment could prevent resistance and improve outcomes [146]. |
Hypoxia-Targeted Therapies | Targeting hypoxia-inducible factors (HIFs) in the tumor microenvironment, in combination with other therapies, could reduce the adaptation of cancer cells to hypoxic conditions, which is often associated with resistance to therapy [147]. |
Epigenetic Modifiers with Chemotherapy | Combining epigenetic therapies, such as DNA methyltransferase inhibitors or histone deacetylase inhibitors with standard chemotherapy could enhance the sensitivity of cancer cells to treatment. Epigenetic modifications often drive resistance, so targeting these changes could overcome resistance mechanisms [148]. |
Combining Epigenetic and Immunotherapies | There is growing interest in combining epigenetic drugs with immunotherapies to increase the immunogenicity of tumors. For example, epigenetic drugs could upregulate the expression of antigens or immune-related genes, making the cancer cells more susceptible to immune attack [148]. |
Next-Generation Targeted Therapies | The development of next-generation small molecule inhibitors that target previously “undruggable” proteins or that have greater specificity and potency is a major focus. These could be used in combination with existing therapies to enhance efficacy and reduce side effects [149]. |
Synthetic Lethality Approaches | Combining drugs that exploit synthetic lethality—where the simultaneous inhibition of two genes or pathways leads to cancer cell death, but inhibition of either alone does not—could provide a powerful strategy against hematologic malignancies with specific genetic alterations [150]. |
Sequential and Adaptive Combinations | Instead of static combination regimens, future therapies might involve adaptive or sequential combinations, where treatments are adjusted based on the real-time monitoring of tumor evolution and resistance patterns. This dynamic approach could help prevent the emergence of drug-resistant clones. |
Dual-Targeting Strategies | Combining two or more drugs that target different aspects of the same pathway or cellular process could prevent the cancer from developing resistance through alternative pathways [145]. |
Big Data for Predictive Modeling | Integrating data from genomics, proteomics, and patient outcomes into predictive models can help forecast which combinations will be most effective for specific patient populations. This approach could lead to the rapid identification of novel combinations that might not have been considered through traditional research methods [151]. |
Targeted Delivery Systems | Advances in drug delivery technologies, such as nanoparticles or conjugated antibodies, could allow for more precise targeting of drug combinations to cancer cells while sparing healthy tissues. This approach could minimize side effects and improve patients’ quality of life during treatment [152]. |
Reducing Off-Target Effects | Combining therapies that have complementary mechanisms of action but non-overlapping toxicity profiles could reduce the cumulative side effects experienced by patients, making long-term treatment more tolerable [153]. |
Master Protocols | Future clinical trials for combinational therapies are likely to involve master protocols where multiple therapies are tested simultaneously across different subtypes of hematologic malignancies. This approach can accelerate the identification of effective combinations [142,143,144]. |
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Lica, J.J.; Pradhan, B.; Safi, K.; Jakóbkiewicz-Banecka, J.; Hellmann, A. Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential. Molecules 2024, 29, 4280. https://doi.org/10.3390/molecules29174280
Lica JJ, Pradhan B, Safi K, Jakóbkiewicz-Banecka J, Hellmann A. Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential. Molecules. 2024; 29(17):4280. https://doi.org/10.3390/molecules29174280
Chicago/Turabian StyleLica, Jan Jakub, Bhaskar Pradhan, Kawthar Safi, Joanna Jakóbkiewicz-Banecka, and Andrzej Hellmann. 2024. "Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential" Molecules 29, no. 17: 4280. https://doi.org/10.3390/molecules29174280
APA StyleLica, J. J., Pradhan, B., Safi, K., Jakóbkiewicz-Banecka, J., & Hellmann, A. (2024). Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential. Molecules, 29(17), 4280. https://doi.org/10.3390/molecules29174280