Table 3.
Rationales for the combination of CAR T cell therapy with targeted therapies and other immunotherapies.
| Category | Mechanisms | Agents | Status | Regimen |
|---|---|---|---|---|
| BTK inhibitor | -Inhibit BCR and development of tumour cells -Ibrutinib also inhibits ITK to promote expansion and cytotoxicity of CAR T |
Ibrutinib | Published clinical trials (89–91) | Prior to, concurrent with and after CAR T Ex vivo |
| Acalabrutinib | Ongoing (NCT04257578; NCT04484012) | Prior to, concurrent with and after CAR T | ||
| Zanubrutinib | Ongoing (NCT05202782) | Prior to, concurrent with and after CAR T | ||
| Bb007 | Ongoing (NCT03274219) | Ex vivo | ||
| PI3K inhibitor | -Maintain less differentiated T cells and promote expansion -Decrease exhaustion marker expression -Increase ratio of CD8/CD4 -Target PI3K pathway in tumour cells |
Duvelisib | Ongoing (NCT05044039; NCT04890236) | Prior to, concurrent with and after CAR T Ex vivo |
| Idelalisib | Preclinical (140) | |||
| LY294002 | Preclinical (99) | Ex vivo | ||
| AKT inhibitor | -Maintain less differentiated T cells | AKTi-1/2 | Preclinical (101, 102) | Ex vivo |
| TKI | -Suppress tonic CAR signal reversibly -Reverse exhaustion by epigenetic remodelling |
Dasatinib | Ongoing (NCT04603872) | Pulsed administration after CAR T infusion Ex vivo |
| GSK-3β inhibitor | -Maintain less differentiated T cells and promote expansion | TWS119 | Ongoing (NCT01087294) | Ex vivo |
| P38 inhibitor | -Play central regulatory role in T cells expansion, differentiate, oxidative and genomic stress | BIRB796 | Preclinical (141) | Ex vivo |
| Antioxidant | -Scavenge ROS and promote stem memory T cells formation | N-acetylcysteine | Ongoing (NCT05081479) | Prior to, concurrent with and after CAR T Ex vivo |
| FasL blockade | -Prevent AICD in CAR T | Asunercept | Preclinical (142) | After CAR T |
| Cytokines | -Promote T cells expansion, memory maintenance and cytotoxic potential | IL-15 and IL-7 | Ongoing (NCT02652910; NCT02992834) | Ex vivo |
| NKTR-255 | Ongoing (NCT03233854; NCT05359211) | Concurrent with and after CAR T | ||
| NT-I7 | Ongoing (NCT05075603) | After CAR T | ||
| IL-15 and IL-21 | Preclinical (120) | Concurrent with and after CAR T | ||
| GSI | -Inhibit cleavage and downregulation of BCMA | JSMD194 | Ongoing (NCT04855136; NCT03502577) | Concurrent with and after BCMA CAR T |
| PKC inhibitor | -Upregulate CD22 expression | Bryostatin 1 | Preclinical (29, 143) | Prior to, concurrent with and after CD22 CAR T |
| Bcl-2 inhibitor | -Sensitize tumour cells by inhibiting anti-apoptotic Bcl-2 family proteins including Bcl-2, Mcl-1 and Bcl-xL | Venetoclax | Published clinical trial (144); Ongoing (NCT04640909) |
Prior to CAR T |
| ABT-737 | Preclinical (115) | Prior to and concurrent with CAR T | ||
| S63845 | Preclinical (113) | Prior to CAR T | ||
| COX-2 inhibitor | -Sensitize tumour cells to CAR T killing | Celecoxib | Preclinical (136) | Prior to CAR T |
| SMAC mimic | -Inhibit IAPs and sensitize tumour cells to CAR T killing | Birinapant; AT-406; LCL-161 | Preclinical (145) | Prior to, concurrent with and after CAR T |
| DNMT inhibitor | -Inhibit abnormal DNA methylation in tumour cells -Upregulate tumour antigen expression -Reverse CAR T exhaustion |
Decitabine | Ongoing (NCT04697940; NCT04850560; NCT04553393) | Prior to, concurrent with and after CAR T Ex vivo |
| Azacitidine | Preclinical (132, 133) | |||
| HDAC inhibitor | -Induce apoptosis of tumour cells -Upregulate tumour antigen expression -Sensitive tumour cells to CAR T killing |
Chidamide LBH589; SAHA; Panobinostat; entinostat |
Ongoing (NCT05370547; NCT04337606) Preclinical (136) |
Prior to CAR T Prior to CAR T |
| BET inhibition | -Inhibit BRD4 to reverse differentiation of CAR T | JQ1 | Preclinical (138) | After CAR T |
| IDO inhibitor | -Target immunosuppressive metabolites in TME | 1-MT | Preclinical (37) | Prior to, concurrent with and after CAR T |
| GM-CSF inhibitor | -Inhibit immunosuppressive cells | Lenzilumab | Ongoing (NCT04314843) | After CAR T |
| Immuno-modulator | -Enhance cytotoxicity -Maintain memory phenotype -Skew Th2 towards Th1 -Increase immune synapse |
Lenalidomide | Published clinical trials (146–148) Ongoing (NCT03070327; NCT05032820; NCT04133636) |
Prior to, concurrent with and after CAR T |
| CC-122; CD-220; CC-99282 | Ongoing (NCT03310619) | Prior to, concurrent with and after CAR T | ||
| Anti-PD-1 mAb | -Block the inhibitory molecule PD-1 | Pembrolizumab | Published clinical trials (149–151); Ongoing (NCT03287817; NCT02935257) |
Prior and after CAR T |
| Nivolumab | Published clinical trials (152); Ongoing (NCT05385263; NCT05352828; NCT05310591; NCT03310619) |
Prior to, concurrent with and after CAR T | ||
| Tislelizumab | Ongoing (NCT04381741; NCT04539444) | Concurrent with and after CAR T | ||
| Anti-PD-L1 mAb | -Block the inhibitory molecule PD-L1 | Atezolizumab | Published clinical trial (153); | After CAR T |
| Durvalumab | Published clinical trial (154, 155); Ongoing (NCT03310619) | Prior to, concurrent with and after CAR T | ||
| Anti-CTLA-4 mAb | -Block the inhibitory molecule CTLA-4 | Ipilimumab | Ongoing (NCT00586391) | After CAR T |
| Anti-TIGIT mAb | -Block the inhibitory molecule TIGIT | BMS-986207 | Preclinical (156) | After CAR T |
| Monoclonal antibody | -Induce tumour death by ADCC and CDC -Target immunosuppressive cells in TME by CD38 mAb |
Rituximab | Published clinical trial (47); Ongoing (NCT04002401) | Prior to, concurrent with and after CAR T for B-NHL |
| Obinutuzumab | Published clinical trial (47); Ongoing (NCT04889716) | Prior to and concurrent with CAR T for B-NHL | ||
| Daratumumab | Published clinical trial (157) | Prior to CAR T for MM | ||
| ADC | -Bind to tumour surface antigen and release cytotoxic agents | Polatuzumab vedotin | Published clinical trial (158); Ongoing (NCT05260957) | Prior to CAR T for B-NHL |
| Inotuzumab ozogamicin | Published clinical trial (159) | Prior to CAR T for B-ALL | ||
| Brentuximab vedotin | Published clinical trial (10) | Prior to CAR T for B-NHL | ||
| BiTE | -Bind to T cells and tumour cells simultaneously to further trigger anti-tumour effect of T cells | Mosunetuzumab | Published clinical trial (160) Ongoing (NCT04889716, NCT05260957) |
Prior to and after CAR T for B-NHL |
| Glofitamab | Published clinical trial (161); Ongoing (NCT04889716) |
Prior to and after CAR T for B-NHL | ||
| Blinatumomab | Published clinical trial (162–164) | Prior to CAR T for B-ALL |
BTK, Bruton’s tyrosine kinase; BCR, B cell receptor; CAR, Chimeric antigen receptor; PI3K, Phosphatidylinositol-3-kinase; TKI, tyrosine kinase inhibitor; GSK-3β, glycogen synthase kinase-3β; ROS, reactive oxygen species; AICD, activation-induced cell death; GSI, γ-secretase inhibitor; BCMA, B-cell maturation antigen; PKC, protein kinase C; Bcl-2, B-cell lymphoma-2; Mcl-1, myeloid leukaemia 1; COX-2, cyclooxygenase-2; SMAC, second mitochondria-derived activator of caspases; IAPs, inhibitor of apoptosis family of proteins; DNMT, DNA methyltransferase inhibitor; HDAC, Histone deacetylase; BET, bromodomain and extraterminal domain; IDO, indoleamine 2,3-dioxygenase; 1-MT, 1-methyl-d-tryptophan; TME, tumour microenvironment; GM-CSF, granulocyte-macrophage colony-stimulating factor; PD-1, programmed-cell-death-1; mAb, monoclonal antibody; PD-L1, PD-ligand 1; CTLA-4, Cytotoxic T lymphocyte-associated antigen-4; TIGIT, T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain; Th, T helper; CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent T-cell-mediated cytotoxicity; ADC, antibody-drug conjugate; BiTE, bispecific T-cell engager.