Table 1.
Selection of clinical trials in cancer immunotherapy involving T cell targeting nanodrugs and biomaterials.
| Formulation | Mechanism of action | Study | Study description | Arms and Interventions | Results | Ref |
|---|---|---|---|---|---|---|
| Directly T cell addressing NP | ||||||
| 1. CAR-T cell therapy | ||||||
| anti-VEGFR2 CAR-T cells | Targeting VEGFR2 as tumor antigen | NCT01218867 | Phase I/II trial: 24 patients with metastatic, refractory cancer | Lymphodepleting conditioning with cyclophosphamide, aldesleukin, and fludarabine, followed by different doses of anti-VEGFR2 CAR-T cells | Terminated due to PD in 23/24 patients and AE in 95.8% of patients | - |
| anti-GD2 CAR-T cells | Targeting GD2 as tumor antigen and including a suicide switch in case of toxicity (ICD9) | NCT02107963 | Phase I trial: 15 patients with refractory GD2+ tumors | Lymphodepleting conditioning with cyclophosphamide, followed by different doses of anti-GD2 CAR-T cells; If unacceptable toxicity occurs AP1903 may be administered | Results pending | (99) |
| anti-GD2 CAR-T cells | Targeting GD2 as tumor antigen; C7R gene is added to increase the CAR-T cell survival | NCT03635632 | Phase I trial: 94 patients with refractory or relapsed GD2+ solid cancers | Lymphodepletion with cyclophosphamide and fludarabine, followed by different doses of anti-C7R-GD2.CAR-T cells | still recruiting | - |
| anti-CD70 CAR-T cells | Targeting CD70 as tumor antigen | NCT02830724 | Phase I/II trial: 124 patients with refractory or relapsed CD70 positive solid tumors | Lymphodepletion with cyclophosphamide fludarabine, and aldesleukin followed by different doses of anti-hCD70 CAR-T cells | still recruiting | – |
| B7-H3 targeting CAR-T cells | Targeting B7H3 as tumor antigen | NCT04483778 | Phase I trial: 68 patients with relapsed or refractory B7H3 expressing advanced solid tumors | Arm A: Autologous T-cells genetically modified to express an B7H3-specific CAR Arm B: Autologous T-cells genetically modified to a bispecific B7H3xCD19 CAR | still recruiting | - |
| anti-gp100 CAR-T cells | Targeting gp100 as melanoma antigen | NCT03649529 | Early phase I trial: 6 patients with relapsed or refractory gp100 positive melanoma | Patients undergo leukapheresis to isolate T cells; these will be modified and applied as GPA-TriMAR CAR-T cells | still recruiting | - |
| anti-NY-ESO-1 CAR-T cells | Targeting NY-ESO-1 as tumor antigen | NCT03638206 | Phase I/II trial: 73 patients with refractory advanced cancer positive for NY-ESO-1, CD19 and other antigens | Different conditions depending on tumor entity. Following treatment with cyclophosphamide or fludarabine patients receive different CAR-T cells including anti-NY-ESO1 | still recruiting | – |
| CD20 CAR-T cell | Targeting CD20 as melanoma antigen | NCT03893019 | Early phase I trial: 15 patients with refractory, unresectable stage III or metastatic stage IV melanoma | Different doses of anti-CD20 CAR-T cells (MB-CART20.1) | still recruiting | – |
| anti-IL13Ra CAR-T cells | Targeting IL13Ra as melanoma antigen | NCT04119024 | Phase I trial: 24 patients with refractory, unresectable stage III or metastatic stage IV melanoma with confirmed IL-13Ra expression | Lymphodepletion with cyclophosphamide and fludarabine phosphate, followed by treatment with recombinant Interleukin-2, and IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing T Cells | still recruiting | – |
| 2. Other | ||||||
| Lipid Nanoparticle encapsulating mRNA encoding OX40L, IL-23, and IL-36γ (mRNA-2752) | T cell activation and stimulation following ligation with OX40L and treatment with IL-23 and IL-36γ | NCT03739931 | Phase I: 264 patients with refractory, advanced or metastatic disease | Arm A: intratumoral mRNA-2752 monotherapy; Arm B: intratumoral mRNA-2752 + durvalumab; Arm C: intratumoral mRNA-2752 alone or in combination with durvalumab | still recruiting, but preliminary results showing low efficacy with 1 partial response among 17 patients | (100) |
| Lipid nanoparticle encapsulating mRNA encoding OX40L (mRNA-2416) | Enhanced T cell activity, IFN-γ and TNF-α synthesis; upregulation of activation molecules CD25, 4-1BB, OX40 | NCT03323398 | Phase I/II trial: 117 patients with advanced, refractory cancer | Arm A: Intratumoral mRNA-2416 monotherapy Arm B: Intratumoral mRNA-2416 in combination with durvalumab |
active, but not recruiting; results pending | – |
| Saline formulated mixture of 4 mRNA encoding GM-CSF + IFNa2b + IL-12 single chain + IL-15 (SAR441000) | Antigen-specific T cell expansion, increased infiltration by Granzyme B T cells, formation of immune memory, Interferon-γ induction | NCT03871348 | Phase I trial: 231 patients with advanced anti-PD-1 naïve and refractory solid tumors | Different treatment arms including monotherapy with intratumoral SAR441000 and combination of cemiplimab and intratumoral SAR441000 | still recruiting, but preliminary results showing no dose limiting toxicities, but anti-tumor activity in some patients | (101) |
| Liposomal nanodrug delivering MUC1 lipid BLP24 and Monophosphoryl Lipid A (Tecemotide; L-BLP25, StimuVax) | Induction of Th1 polarization and CD8 T cell responses | NCT01462513 | Phase II trial: 122 patients with CRC after curative resection of hepatic metastasis | Arm A: L-BLP25 monotherapy Arm B: placebo |
Failed to reach primary endpoints; Median PFS: 6.1 vs 11.4 months; median OS: 62.8 vs not reached; severe AE: 29.1% vs 26.2% | |
| Artificial antigen presenting cells (aAPC) to generate Melan-A/MART1 specific T cells | Using aAPC to generate melanoma-specific cytotoxic T cells upon leukapharesis | NCT00512889 | Phase I trial: 9 patients with unresectable stage III or metastatic stage IV melanoma and MART-1/ Melan-A expression | Treatment either with aAPC generated MART-1/Melan-A specific CTL or treatment with combined aAPC-generated CTL plus GM-CSF and irradiation of cutaneous melanoma lesions | No results posted; aAPC educated CTL could survive for prolonged periods, trafficked to the tumor and established antitumor immunologic memory | (102) |
| aAPC to expand multiple antigen-specific T cells (MASE-T) | Using aAPCS scaffolds for antigen-driven T cell expansion and enrichment of T cells specific for melanoma antigens | NCT04904185 | Phase I trial: 12 patients with ICB-refractory metastatic melanoma | Part A: Lymphodepletion with fludarabine and cyclophosphamide prior to ex-vivo, aAPC expanded T cell transfer; Part B: Lymphodepletion with fludarabine and cyclophosphamide prior to ex-vivo, aAPC expanded T cell transfer in combination with pembrolizumab | still recruiting | - |
| Indirectly T cell targeting NP | ||||||
| 1. Protein based NP | ||||||
| Nanoformulation of paclitaxel which is incorporated in albumin nanoparticles as a carrier | Enhanced infiltration of CTL and DC and reduction of Treg numbers; contributes to TAM polarization towards M1 phenotype | NCT02425891 | Phase III trial: 902 patients with unresected triple-negative breast cancer | Arm A: atezolizumab plus nab-paclitaxel Arm B: Placebo plus nab-paclitaxel |
Median PFS: 7.2 vs 5.5 months, p=0.002; median OS: 21.3 vs 17.6 months, p=0.08; AE that led to treatment discontinuation: 15.9 vs 8.2% | (103, 104) |
| Nanoformulation of paclitaxel which is incorporated in albumin nanoparticles as a carrier | Enhanced infiltration of CTL and DC and reduction of Treg numbers; contributes to TAM polarization towards M1 phenotype | NCT02367781 | Phase III trial: 723 patients with chemotherapy-naïve patients with stage IV NSCLC | Arm A: nab-paclitaxel plus carboplatin in combination with atezolizumab Arm B: nab-paclitaxel plus carboplatin | Median OS: 18.6 vs 13.9 months (p=0.033); median PFS: 7.0 vs 5.5 months (p<0.0001), serious TAE were reported in 24% vs 13% of patients | (105) |
| 2. Polymer-drug/protein conjugates | ||||||
| PEGylated liposomal formulation of doxorubicin | Induction of ICD, depletion of myeloid-derived suppressor cells; enhanced cancer-cell susceptibility to CTL-released granzyme B | NCT02580058 | Phase III trial: 566 patients with platinum-resistant ovarian cancer | Arm A: avelumb in combination with Doxil Arm B: Doxil monotherapy Arm C: avelumab monotherapy |
Median PFS: 3.7 vs 3.5 months (Arm A vs B p=0.03) vs 1.9 months (Arm C); median OS: 15.7 vs 13.1 months (p=0.021) vs 11.8 months; Serious TAE were reported in 18% vs 11% vs 7 % | (106) |
| Nanoliposomal PEGylated Irinotecan | Depletion of regulatory T cells and upregulation of MHC-I and PD-L1 expression, resulting in enhanced anti-tumor activity | NCT01494506 | Phase III trial: 417 patients with gemcitabine-resistant, metastatic pancreatic cancer | Arm A: Nanoliposomal irinotecan Arm B: 5-FU plus leucovorin Arm C: Nanoliposomal irinotecan in combination with 5-FU and leucovorin |
Median PFS: 3.1 vs 1.5 (p=0.0001) vs 1.6 months (p=0.1); Median OS: 6.1 vs 4.2 vs 4.9 months (Arm B vs C vs A; p=0.012); Serious TAE were reported in 48% vs 45% vs 61% | (107) |
| 3. Liposomal or lipid-based NP | ||||||
| Formulation of RNA-drug products against the melanoma antigens NY-ESO-1, tyrosinase, MAGE 3 and TPTE with liposomes that form RNA-lipoplexes (RNA-LPX; BNT-111) | DC maturation and activation, induction of antigen-specific T cell responses | NCT02410733 | Phase I trial: 119 patients with advanced, refractory melanoma | Lipo-MERIT + nivolumab vs Lipo-MERIT monotherapy | still active but not recruiting; interim data: Monotherapy arm: ORR of 4/25 and DCR of 11/25; Combination therapy: ORR of 6/17 |
(108, 109) |
| mRNA-4157 encapsulated in lipids | DC maturation and activation, induction of antigen-specific T cell responses | NCT03313778 | Phase I trial: 142 patients with locally advanced or metastatic solid malignancies including NSCLC, CRC, HNSCC, urothelial carcinoma or melanoma | Arm A: mRNA-4157 monotherapy Arm B: mRNA-4157 monotherapy in combination with pembrolizumab |
still recruiting; interim analysis revealed no disease-limiting toxicities or serious TAE; Arm A: 11/13 remained disease free for median of 10 months Arm B: PR in 5/20 patients and SD in 6/20 patients |
(110) |
| mRNA-4157 encapsulated in lipids | DC maturation and activation, induction of antigen-specific T cell responses | NCT03897881 | Phase II trial: 157 patients with high-risk melanoma upon complete resection of lymph node metastasis | Arm A: mRNA-4157 in combination with pembrolizumab Arm B: pembrolizumab monotherapy |
active, but interim results pending | – |
| Paclitaxel loaded lipid core NPs | DC maturation and T cell activation | – | Phase II trial: 14 patients with refractory ovarian carcinoma | Single-group arm treated with paclitaxel carried in non-protein lipid core nanoparticles (PTX-LDE) | Median PFS: 3.0 months with no major toxicities | (111, 112) |
| Eribulin encapsulated in liposomal formulation (E7389) | Vascular remodeling and facilitation of immune cell recruitment into the tumor | NCT04078295 | Phase Ib/II trial: 116 patients with advanced, nonresectable or recurrent solid tumor | Arm A: E7389-LF in combination with nivolumab | active, but not recruiting; interim data: ORR was 17.6% and DCR was 79.4%; median PFS: 3.7 months; median OS: 7.6 months | (113) |
| STP705 Liposomal formulation of two siRNA oligonucleotides targeting TGF-ß1 and COX-2 mRNA | Increased T effector cell activation, cytokine secretion and proliferation | NCT04844983 | Phase II trial: 100 patients with cutaneous squamous cell carcinoma in-situ | Arm A: Intralesional STP705 Arm B: Placebo Saline |
still recruiting | – |
| Formulation of RNA-drug products against 5 antigens with liposomes that form RNA-lipoplexes (RNA-LPX; W_pro1 cancer vaccine) | DC maturation and activation, induction of antigen-specific T cell responses | NCT04382898 | Phase I/II trial: 130 patients with metastatic castration-resistant prostate carcinoma | Arm A: W_pro1 in combination with cemiplimab Arm B: W_pro 1 monotherapy |
still recruiting | (114) |
| Formulation of RNA-drug products against 3 antigens with liposomes that form RNA-lipoplexes (RNA-LPX; W_ova1 Vaccine) | DC activation and T cell stimulation | NCT04163094 | Phase I trial: 10 patients with ovarian carcinoma eligible for neo-adjuvant chemotherapy | Single-treatment group: W_ova 1 monotherapy during neo-adjuvant chemotherapy and subsequent adjuvant chemotherapy with carboplatin/paclitaxel | still recruiting | – |
| Formulation of RNA-drug products against HPV 16 with liposomes that form RNA-lipoplexes (RNA-LPX; HPV16 E7; HARE40) | Priming and activation of effector and memory T cells | NCT03418480 | Phase I/II trial: 44 patients with HPV16+, refractory HNSCC, anogenital, cervical or penile carcinoma | Arm A: HPV16 E7 RNA-LPX monotherapy Arm B: HPV16 E7 RNA-LPX in combination with anti-CD40 |
active, but not recruiting; interim data pending | (115) |
| IVAC_W_bre1_uID | DC activation and T cell stimulation | NCT02316457 | Phase I trial: 42 patients with pT1, N0, M0 triple-negative breast cancer | Arm 1: IVAC_W_bre1_uiD monotherapy Arm 2: IVAC_W_bre1_uID/IVAC_M_uID personalized vaccine monotherapy Arm 3: IVAC_W_bre1_uID + RBLTet.1 with 3 variant RNA |
active but not recruiting; interim data pending | (116) |
| Lipid-formulated mRNA with tumor and lysosome-associated membrane glycoprotein-fused cytomegalovirus pp65 mRNA | Induction of ICD, DC activation and T cell stimulation | NCT04573140 | Phase I trial: 28 patients with newly diagnosed pediatric high-grade gliomas and adult glioblastoma | Single-treatment trial: RNA-loaded lipid particles with total tumor mRNA and pp65 | still recruiting | – |
| Lipid-formulated mRNA encoding for different kRAS mutations (mRNA-5671/V941) | Induction of ICD, DC activation and T cell stimulation | NCT03948763 | Phase I trial: 100 patients with KRAS-mutant advanced or metastatic NSCLC, CRC or pancreatic adenocarcinoma | Arm A: mRNA-5671 monotherapy Arm B: mRNA-5671 in combination with pembrolizumab |
active, but results pending | – |
| Lipid-formulated NP with individualized tumor neoantigens (RNA-LPX; RO7198457) | DC activation and T cell stimulation | NCT03289962 | Phase Ia/b trial: 272 patients with locally advanced or metastatic, refractory solid tumors | Arm A: RO7198457 monotherapy Arm B: RO7198457 in combination with atezolizumab |
active, but not recruiting; interim data of 26 patients showed 1 CR and 11 patients with SD | (117) |
| Lipid-formulated NP with individualized tumor neoantigens (RNA-LPX; RO7198457) | DC activation and T cell stimulation | NCT03815058 | Phase II trial: 131 patients with previously untreated advanced melanoma | Arm A: pembrolizumab monotherapy Arm B: RO7198457 in combination with pembrolizumab |
active, but not recruiting, interim data pending | – |
| 4. Viral vectors | ||||||
| Imlygic in combination with pembrolizumab | Tumor lysis, DC activation; T cell stimulation and infiltration | NCT04068181 | Phase II trial: 72 patients with stage IIIB-IV melanoma who have progressed on anti-PD-1 therapy | Single-arm treatment: intralesional Talimogene laherparepvec in combination with pembrolizumab | active, but results still pending | |
| RP1 oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP-R) and GM-CSF | Tumor lysis, DC activation; T cell stimulation and infiltration | NCT04050436 | Phase II trial: 180 patients with advanced cutaneous squamous cell carcinoma of the skin | Arm A: cemiplimab in combination with RP1 Arm B: cemiplimab monotherapy |
still recruiting | (118) |
| 5. Inorganic Nanoparticles | ||||||
| Hafnium oxide nanoparticles (NBXTR3) | Enhance ICD via electron production, T cell activation |
NCT03589339
and NCT02379845 |
Phase I trial: 60 patients with locally advanced cancers treated with anti-PD-1 therapy and phase II/III trial with 180 patients with advanced soft-tissue sarcoma | Arm A: intratumoral injection of NBTXR3 followed by radiation and anti-PD-1 therapy with nivolumab or pembrolizumab Arm B: radiotherapy followed by anti-PD-1 monotherapy |
Results from phase II/III trial: pCR in 16% vs 8% (p=0.044); serious AE 39% vs 30% | (119, 120) |
aAPC, artificial antigen presenting cells; (p)CR, (pathological) complete response; CRC, colorectal carcinoma; CTL, cytotoxic T lymphocytes; DC, dendritic cells; DCR, disease-control rate; GD2, disialoganglioside 2; GM-CSF, granulocyte-monocyte colony stimulating factor; HNSCC, head-and-neck squamous cell carcinoma; HPV, human papillomavirus; HSV, herpes simplex virus; ICB, immune-checkpoint blockade; ICD, immunogenic cell death; IFN, interferon; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; (T)AE, (treatment-related) adverse events; TGF-ß, transforming growth factor beta; VEGFR, vascular endothelial growth factor receptor.