Summary of CRISPR-based screening studies that have improved prospective therapeutic regimens within blood cancers
| Clinical drug trials . | CRISPR Screening studies adding value to the drug trials . | |||||
|---|---|---|---|---|---|---|
| Candidate drug . | Class/target . | Clinical trial status/major outcome for completed studies . | Clinical trial identifier . | Company . | Critical outcome from the CRISPR screen . | Reference . |
| CG-806 (luxeptinib) | Small molecule pan-FLT3/pan-BTK multicluster kinase inhibitor | Phase 1 (AML, MDS, CLL, SLL, NHL) | NCT04477291 (AML, MDS), NCT03893682 (CLL, SLL, NHL) | Aptose Biosciences | Preclinical testing of CG-806 resulted in disrupted BCR signaling and an induction of metabolic reprogramming and apoptosis in MCL. | 171 |
| REGN1979 (odronextamab) | CD20xCD3 bispecific Ab | Phase 1 (B-NHL, CLL, R/R B-NHL) | NCT02290951 (NHL, CLL), NCT03888105 (Relapsed or Refractory B-cell NHL) | Regeneron Pharmaceuticals | Cell adhesion molecules like sialophorin limit CD3 bsAb-mediated cell lysis, thereby modulating the cytotoxicty of the CD20xCD3 bsAbs in blood cancers. | 172 |
| Tazemetostat Tazemetostat (in combination with lenalidomide and rituximab) | Tazemetostat (small molecule inhibitor of EZH2) | Accelerated approval for follicular lymphoma Phase 3 (R/R follicular lymphoma) | NCT01897571 NCT04224493 | Epizyme, Inc | Combination therapy incorporating tazemetostat (targeting EZH2) and lenalidomide (targets Ikaros and Aiolos) is synergistic and cytotoxic even in cell lines that are refractory to the treatment with tazemetostat alone. | 168 |
| Ibrutinib (in combination with lenalidomide and DA-EPOCH-R) | Ibrutinib (small molecule inhibitor of BTK) | Highly effective responses for activated B-cell DLBCL in a phase 1/2 clinical trial | NCT02142049 | Pharmacyclics LLC | My-T-BCR form a multiprotein supercomplex that can help stratify patients with DLBCL sensitive or resistant to ibrutinib treatment. | 181 |
| STA 5326 (apilimod) | Small molecule inhibitor of PIKfyve kinase | No clinical improvement in RA in a phase 2a clinical trial Clinical effect observed in Crohn disease in a phase 1/2A clinical trial | NCT00642629 NCT00088062 | Synta Pharmaceuticals Corp | Apilimod was identified as a first-in-class PIKfyve kinase inhibitor for treatment of B-NHL. | 169 |
| SGI-110 (guadecitabine) | A dinucleotide prodrug of decitabine that inhibits DNA methyltransferase | A 40% overall response rate with acceptable toxicity observed in R/R PTCL population treated with the drug in a phase 2 clinical trial | ACTRN12618000028202 | Astex Pharmaceuticals Inc | Presence of RHOAG17V mutations and deletion of histone methyltransferase SETD2 sensitized patients with PTCL to SGI-110. | 182 |
| OTX015 (birabresib, MK 8628) | Small molecule inhibitor of BRD2, BRD3, and BRD4 | Clinical effect of bromodomain inhibition alone may be insufficient to manage the patients with leukemia as per a dose escalation, phase 1 study | NCT01713582 | Oncoethix GmbH | Regulators of monocytic differentiation and aryl-hydrocarbon receptor signaling were identified as determinants of BET inhibitor (such as OTX015) response and can hence be used clinically to identify potential responders to therapy. | 140 |
| DNT cells | Allogeneic double negative T cmitochells | Phase 1 (AML) | NCT03027102, ChiCTR-IPR-1900022795 | University Health Network, Toronto | CRISPR screen identified CD64 as the primary determinant of sensitivity to DNT-based therapy and can consequently be used as a predictive marker for response in AML patients to DNT therapy. | 183 |
| CC-90009 CC-90009 (in combination with Venetoclax, Azacitidine, Gilteritinib) | Small Molecule cereblon E3 ligase modulator | Phase 1 (AML, MDS) Phase 1/2 (AML) | NCT02848001 NCT04336982 | Celgene | ILF2/ILF3 complex and mTOR signaling components govern the cytotoxicity of CC-90009 in AML cells through targeted modulation of cereblon protein expression. | 184 |
| Birinapant (in combination with Pembrolizumab) | Small molecule and peptidomimetic of SMAC and inhibitor of IAP | Phase 1/2 (Solid Tumors) | NCT02587962 | Medivir | SMAC mimetics like Birinapant were identified as potential sensitizers of CD19+ B-cell malignancies to CAR T-cell cytotoxicity. | 150 |
| Clinical drug trials . | CRISPR Screening studies adding value to the drug trials . | |||||
|---|---|---|---|---|---|---|
| Candidate drug . | Class/target . | Clinical trial status/major outcome for completed studies . | Clinical trial identifier . | Company . | Critical outcome from the CRISPR screen . | Reference . |
| CG-806 (luxeptinib) | Small molecule pan-FLT3/pan-BTK multicluster kinase inhibitor | Phase 1 (AML, MDS, CLL, SLL, NHL) | NCT04477291 (AML, MDS), NCT03893682 (CLL, SLL, NHL) | Aptose Biosciences | Preclinical testing of CG-806 resulted in disrupted BCR signaling and an induction of metabolic reprogramming and apoptosis in MCL. | 171 |
| REGN1979 (odronextamab) | CD20xCD3 bispecific Ab | Phase 1 (B-NHL, CLL, R/R B-NHL) | NCT02290951 (NHL, CLL), NCT03888105 (Relapsed or Refractory B-cell NHL) | Regeneron Pharmaceuticals | Cell adhesion molecules like sialophorin limit CD3 bsAb-mediated cell lysis, thereby modulating the cytotoxicty of the CD20xCD3 bsAbs in blood cancers. | 172 |
| Tazemetostat Tazemetostat (in combination with lenalidomide and rituximab) | Tazemetostat (small molecule inhibitor of EZH2) | Accelerated approval for follicular lymphoma Phase 3 (R/R follicular lymphoma) | NCT01897571 NCT04224493 | Epizyme, Inc | Combination therapy incorporating tazemetostat (targeting EZH2) and lenalidomide (targets Ikaros and Aiolos) is synergistic and cytotoxic even in cell lines that are refractory to the treatment with tazemetostat alone. | 168 |
| Ibrutinib (in combination with lenalidomide and DA-EPOCH-R) | Ibrutinib (small molecule inhibitor of BTK) | Highly effective responses for activated B-cell DLBCL in a phase 1/2 clinical trial | NCT02142049 | Pharmacyclics LLC | My-T-BCR form a multiprotein supercomplex that can help stratify patients with DLBCL sensitive or resistant to ibrutinib treatment. | 181 |
| STA 5326 (apilimod) | Small molecule inhibitor of PIKfyve kinase | No clinical improvement in RA in a phase 2a clinical trial Clinical effect observed in Crohn disease in a phase 1/2A clinical trial | NCT00642629 NCT00088062 | Synta Pharmaceuticals Corp | Apilimod was identified as a first-in-class PIKfyve kinase inhibitor for treatment of B-NHL. | 169 |
| SGI-110 (guadecitabine) | A dinucleotide prodrug of decitabine that inhibits DNA methyltransferase | A 40% overall response rate with acceptable toxicity observed in R/R PTCL population treated with the drug in a phase 2 clinical trial | ACTRN12618000028202 | Astex Pharmaceuticals Inc | Presence of RHOAG17V mutations and deletion of histone methyltransferase SETD2 sensitized patients with PTCL to SGI-110. | 182 |
| OTX015 (birabresib, MK 8628) | Small molecule inhibitor of BRD2, BRD3, and BRD4 | Clinical effect of bromodomain inhibition alone may be insufficient to manage the patients with leukemia as per a dose escalation, phase 1 study | NCT01713582 | Oncoethix GmbH | Regulators of monocytic differentiation and aryl-hydrocarbon receptor signaling were identified as determinants of BET inhibitor (such as OTX015) response and can hence be used clinically to identify potential responders to therapy. | 140 |
| DNT cells | Allogeneic double negative T cmitochells | Phase 1 (AML) | NCT03027102, ChiCTR-IPR-1900022795 | University Health Network, Toronto | CRISPR screen identified CD64 as the primary determinant of sensitivity to DNT-based therapy and can consequently be used as a predictive marker for response in AML patients to DNT therapy. | 183 |
| CC-90009 CC-90009 (in combination with Venetoclax, Azacitidine, Gilteritinib) | Small Molecule cereblon E3 ligase modulator | Phase 1 (AML, MDS) Phase 1/2 (AML) | NCT02848001 NCT04336982 | Celgene | ILF2/ILF3 complex and mTOR signaling components govern the cytotoxicity of CC-90009 in AML cells through targeted modulation of cereblon protein expression. | 184 |
| Birinapant (in combination with Pembrolizumab) | Small molecule and peptidomimetic of SMAC and inhibitor of IAP | Phase 1/2 (Solid Tumors) | NCT02587962 | Medivir | SMAC mimetics like Birinapant were identified as potential sensitizers of CD19+ B-cell malignancies to CAR T-cell cytotoxicity. | 150 |
BCR, B-cell receptor; BET, bromodomain and extraterminal; bsAb, bispecific antibody; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; DA-EPOCH-R, dose adjusted EPOCH-R (etoposide phosphate, prednisone, vincristine sulfate [Oncovin], cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin], and rituximab); DNT, double negative T cell; IAP, inhibitor of apoptosis protein; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; My-T-BCR, MYD88L265P - TLR9 - BCR supercomplex; MYD88, myeloid differentiation primary response 88; TLR9, Toll-like receptor 9; PIKfyve, phosphatidylinositol-3-phosphate 5-kinase; PTCL, peripheral T-cell lymphoma; RA, rheumatoid arthritis; R/R, relapsed or refractory; SLL, small lymphocytic lymphoma; SMAC, second mitochondrial-derived activator of caspases.