Table 2.
Overview of Ibrutinib in combination therapies
| Combination | Disease | Model | Rationale | Effect | Reference |
|---|---|---|---|---|---|
| γ-secretase inhibitors (crucial protease in Notch signaling) |
CLL | CLL patient cells | NOTCH1 signaling is related to resistance to therapy in B-CLL. | Combination therapy showed enhanced cytotoxicity and reduced CXCR4 expression and functions (response to SDF-1α) | [255] |
| Histone Deacetylase (HDACs) Inhibitor | CLL | - MCL cell line - mice engrafted with TCL-1 splenocytes |
HDACs increase transcription of miRNA that repress BTK | HDAC induced increase in target miRNA and a decrease in BTK RNA; combination exhibited higher cytotoxicity than either drug alone; reduction of p-BTK and total BTK protein. | [69] |
| Anti-CD19 CAR T Cells (CART19) | MCL | MCL Xenograph model |
Efficient B cell depletion | Long-term remission in 80–100% of mice (treated with CART19 only: 0–20% of mice) | [245] |
| Ethacridine (Poly(ADP-ribose) glycohydrolase inhibitor) | AML | SCID mice injected s.c. with OCI-AML2 cells | Result of a drug screening | High decrease of OCI-AML2 cell growth (more than with either drug alone). Suggested mechanism: increased intracellular ROS production in cells treated with combination. | [256] |
| ND-2158 (IRAK4 inhibitor) |
ABC-DLBCL | - ABC-DLBCL cell lines OCI-Ly10 and TMD8 - OCI-Ly10 xenografts |
MYD88-IRAK4 signaling is important for ABC- DLBCL viability | Combination was more effective than ND-2158 alone in inhibiting IKK activity, enhancing apoptosis, and blocking tumor growth in mice. | [257] |
| PU-H71 (Binds to tumor enhanced HSP90 complexes) |
ABC-DLBCL | DLBCL cell lines (HBL-1 and TMD8) | teHSP90 complexes are associated with tumor survival. | PU-H71 disrupts teHSPP90 (but not house-keeping fractions associated with HSP90). Synergistic effect, with ~ 95% tumor growth inhibition; decreased NF-kB activity |
[258] |
| TP-0903 (AXL inhibitor) |
CLL | Patient CLL cells prior to or after ibrutinib therapy | AXL contributes to oncogenic survival in CLL. | TP-093 disrupts the activity of AXL; Induction of cell-death in a dose-dependent fashion | [259] |
| B-PAC-1 (pro-caspase activating compound) |
CLL | B cells from patients on ibrutinib therapy | B-PAC activates caspases dimers | Induced cytotoxicity in leukemic cells | [259] |
| Carfilzomib (proteasome inhibitor) |
CLL | Primary CLL patient samples MEC-1 and MEC2 cell lines | Upregulation of pro-apoptotic transcription factor CHOP | Combination showed an additive cytotoxic effect; Carfilzomib induced a pro-apoptotic response involving Noxa, MCL-1, Bax, and Bak and intrinsic and extrinsic caspase pathways | [260] |
| Selinexor (Exportin inhibitor) |
CLL | Primary CLL patient samples | Selinexor disrupts BCR signaling via BTK depletion | Combination showed synergistic cytoxicity. Selinexor overcomes resistance to Ibrutinib (also in patient cells with C481S mutation) | [261] |
| Anti-PDL1 antibody (Negative regulator of T cell function) |
B cell lymphoma (A20) | - BALB/c mice inoculated with A20 B cells - A20 B cells are resistant to Ibrutinib |
Blocking immune checkpoints can enhance the anti-tumor response | Anti-PDL-1 treatment alone delayed tumor growth and slightly increased mouse survival Combination with anti-PDL-1 cured ~ 50% of the mice, delayed tumor growth and prolonged survival in the remaining mice, and increased IFN-γ producing T-cells |
[243] |
| ABT-199 (BCL-2 antagonist) |
CLL | Ex vivo samples from CLL patients on ibrutinib | CLL samples show enhanced BCL-2 expression | Ibrutinib enhances ABT-199 cytotoxicity, both in unstimulated and in αIgM-stimulated CLL cells from. ABT-199 action correlated with a decline in expression of anti-apoptotic MCL-1 | [262] |
| ABT-199 (BCL-2 antagonist) |
MCL | CCMCL1 MCL cell line |
MCL cells show enhanced BCL-2 expression | Combination results in decrease of p-BTK and p-AKT. Downregulation of both BCL2 and MCL1. ABT-199 and Ibrutinib target non-overlapping pathway s | [263] |
| Bortezomib (proteosome inhibitor) and lenalidomide chemotherapy | MM | Cells from MM patients and MM cell lines | Blocking BTK to downregulate NF-kB activation and cell survival | Ibrutinib increased the cytotoxicity of bortezomib and lenalidomide in both patient cells and cell lines | [264] |
| CpG (TLR9 ligand) |
B-cell lymphoma | Murine pre-B cell (H11) and B cell lymphoma lines (BL3750, A20) | CpG activates APCs and thereby induces T cell activation | Combination of ibrutinib and intratumoral CpG resulted in tumor regression and resistance, whereby IFNy-producing CD4 and CD8 T are essential | [265] |
| Sudemycin D1 (spliceosome modulator) | CLL | Primary CLL cells (from SF3B1-unmutated and mutated cases) | SF3B1 is frequently mutated in CLL, and correlates with aggressiveness | Combination results in enhanced apoptosis of M-CLL and U-CLL. Effect is related to IBTK splicing. Sudemycin D1 downregulates anti-apoptotic MCL-1 through alternative splicing | [266] |
| BAY80–6946 (PIK3 inhibitor) INK128 (mTOR inhibitor) |
PCNSL | - Xenograft model from CD79B-mutant biopsies | CARD11 domain mutations increase the activity of the PIK3-mTOR axis | In cell lines, cell death was induced with both combinations of drugs | [177] |
| Idelalisib (PI3K inhibitor) |
DLBCL | - Cell lines. - Mouse TMD8 xenograft model |
PI3K is upstream regulator of NF-кB pathway. | Cell lines: combination induced 50% apoptosis and inhibited signaling (more than either drug individually). Mouse xenograft: Significant tumor regression |
[267]1 |
| Idelalisib (PI3K inhibitor) |
MCL | MCL cell lines | A more robust blockage of BCR signaling | Inhibition of BCR-stimulated integrin- mediated adhesion; stronger inhibition of adhesion compared to each drug alone | [146]1 |
1In this study, also ONO/GS-4059, the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 and the AKT inhibitor MK-2206 were investigated
CLL Chronic Lymphocytic leukemia, MCL Mantle cell lymphoma, AML Acute Myeloid Leukemia, ABC-DLBCL Activated B-cell Diffuse large B cell Lymphoma, MM Multiple Myeloma, PCNSL Primary central nervous system lymphoma