Table 1.
Overview of trials with dendritic cell (DC)-based immunotherapy in lung cancer.
| Reference | Study population | N | Trial phase | DC subset | Maturation factors | Antigen selection and formulation | Vaccination protocol |
|---|---|---|---|---|---|---|---|
| DC therapy in NSCLC | |||||||
| Fong et al. (35) | Metastatic CRC or NSCLC expressing CEA | 12 (2 with NSCLC) | Phase 1 | Flt3-mobilized circulating DCs Mature |
N/A | CEA peptide | a) 2 vaccinations b) 1-month interval c) i.v. injection d) Maximum dose of 109 cells per vaccination |
| Itoh et al. (36) | Metastatic digestive tract or lung cancer expressing CEA | 10 (2 with lung cancer) | Phase 1 | moDCs Immature |
N/A | CEA peptide | a) 10 vaccinations b) 2-week interval c) i.d. and s.c. injection at the same site in the inguinal region d) Total dose of 2.7 × 107 cells to 1.6 × 108 cells e) IFN-α and TNF-α |
| Nair et al. (37) | Metastatic cancer | 3 (1 with NSCLC) | Phase 1 | moDCs Immature |
N/A | CEA RNA or autologous tumor RNA | a) 4 vaccinations b) 4-week interval c) i.v. and i.d. d) 3 × 106 cells (i.v.) and 1 × 106 cells (i.d.) per vaccination |
| Kontani et al. (38) | Advanced or metastatic breast or lung cancer | 14 (8 with lung cancer) | Phase 1 | moDCs Mature |
N/A | MUC1 antigen or tumor lysate | a) 3 to 12 vaccinations b) 2-week interval c) s.c. or intrapleural d) 4–10 × 106 cells per vaccination |
| Hirschowitz et al. (39, 40) | Stage I-IIIB NSCLC | 16 | Phase 1 | moDCs Mature |
DCTCMF IFN-γ |
Apoptotic bodies of an allogeneic NSCLC cell line that overexpressed HER2/neu, CEA, WT1, MAGE-2, and survivin | a) 2 vaccinations b) 1-month interval c) i.d. injection in the thigh d) Average dose of 9.1 × 107 and 8.2 × 107 cells per vaccination respectively |
| Ueda et al. (41) | Metastatic gastrointestinal or lung adenocarcinoma expressing CEA | 18 (5 with lung cancer) | Phase 1 | moDCs Immature |
N/A | CEA peptide | a) Median number of 9 vaccinations (range, 5–39) b) 2-week interval c) i.d. and s.c. injection at the same site in the inguinal region d) 0.5–5 × 107 cells per vaccination |
| Chang et al. (42) | Stage IV NSCLC with malignant pleural effusion | 8 | Phase 1 | moDCs Mature |
TNF-α | Tumor cell lysate derived from malignant pleural effusion specimens | a) 6 vaccinations b) 1-week interval for the first 4 vaccinations, then twice biweekly c) i.n. injection under sonographic guidance d) Dose not mentioned |
| Morse et al. (43) | Metastatic cancer expressing CEA | 14 (3 with NSCLC) | Phase 1 | moDCs Immature |
N/A | Fowlpox virus encoding CEA and a triad of costimulatory molecules (rF-CEA(6D)-TRICOM) | a) 4 (first cohort) or 8 vaccinations (second cohort) b) triweekly c) s.c. and i.d. injection in the same limb d) Dose not mentioned |
| Hirschowitz et al. (44) | Stage I-IIIB NSCLC | 14 | Phase 1 | moDCs Immature |
N/A | Apoptotic bodies of an allogeneic NSCLC cell line that overexpressed HER2/neu, CEA, WT1, MAGE-2, and survivin | a) 2 vaccinations b) 1-month interval c) i.d. injection in the thigh d) Average dose of 8.2 × 107 and 7.9 × 107 cells per vaccination respectively |
| Mayordomo J et al. (45) | Metastatic cancer | 15 (2 with NSCLC) | Phase 1 | moDCs Immature |
N/A | Autologous tumor lysate | a) 3 vaccinations b) 3-week interval c) i.v. injection d) Median dose of 6.2 × 107 cells per vaccination e) IL-2, INF-α and GM-CSF |
| Um et al. (46) | Stage IIIB-IV NSCLC | 15 | Phase 1 | moDCs Mature |
TNF-α IL-1 IL-6 PGE2 |
Autologous tumor lysate | a) 3 vaccinations and after verification of tolerability 2 subsequent vaccinations b) 2-week interval for the first 3 vaccinations and 1-month interval for the subsequent 2 vaccinations c) i.d. injection d) Maximum dose of 12 × 106 cells per vaccination |
| Perroud et al. (47) | Stage IIIB-IV NSCLC | 5 | Phase 1 | moDCs Mature |
IFN-γ | WT1 peptide CEA peptide MAGE-1 peptide HER-2 peptide |
a) 2 vaccinations b) 2-week interval c) s.c. and i.v. injection in separate arms d) 5 × 107 cells per vaccination |
| Takahashi et al. (48) | Locally advanced or metastatic NSCLC | 62 | Retrospective analysis | moDCs Mature |
OK-432 PGE2 |
Autologous tumor lysate or peptide antigens (WT1, MUC1, CEA) according to the HLA-A pattern. | a) Median number of 10 vaccinations (range, 4–31) b) Biweekly c) i.d. injection near the axillar and/or inguinal lymph nodes d) 1 × 107 cells per vaccination |
| Hu et al. (49) | Stage IIIB-IV NSCLC | 27 | Phase 1 | moDCs Immature |
N/A | Autologous tumor lysate | a) Number of vaccinations not mentioned b) 3-week interval c) i.d. injection d) Average dose of 1 × 107 cells per vaccination |
| Takahashi et al. (50) | Locally advanced or metastatic NSCLC | 260 | Retrospective analysis | moDCs Mature |
OK-432 PGE2 |
WT1 peptide MUC1 peptide |
a) Median number of 7 vaccinations (range, 5–34) b) Biweekly c) i.d. injection near the axillar and/or inguinal lymph nodes d) 1 × 107 cells per vaccination e) OK-432 |
| Li et al. (51) | Stage I-IIIB NSCLC | 16 | Phase 1 | moDCs Mature |
IL-1β IL-6 TNF-α IFN-γ PGE2 Poly I:C |
rMAGE-3 peptide rSurvivin peptide |
a) 2 vaccinations b) 1-month interval c) i.d. d) 9.1 × 107 cells and 8.2 × 108 cells per vaccination respectively |
| Lee et al. (52) | Stage III-IV NSCLC | 16 | Phase 1 | moDCs Immature |
N/A | Viral vector (Ad.CCL21-DC) | a) 2 vaccinations b) 1-week interval c) CT- or bronchoscopy guided i.t. injection d) Maximum dose of 3 × 107 cells per vaccination |
| Teramoto et al. (53) | Stage IIIB-IV NSCLC | 40 | Retrospective analysis | moDCs Mature |
OK-432 | MUC1 peptide | a) range, 1–42 vaccinations b) 2-week interval c) s.c. injection d) 1 × 107 cells per vaccination |
| Ge et al. (54) | Resected stage I-IIIA NSCLC | 15 | Phase 1 | moDCs Mature |
Flagellin SOSC1-specific small interfering RNA |
MUC1 peptide Survivin peptide |
a) 3 vaccinations b) 1-week interval c) i.v. injection d) 1 × 106,1 × 107 or 8 × 107 cells per vaccination |
| DC/CIK therapy in NSCLC | |||||||
| Li et al. (55) | Stage I-IIIA NSCLC | 84 (42 received DC/CIK) | Phase 1/2 | moDCs Mature |
N/A | Autologous tumor lysate | a) 4 vaccinations b) 1-month interval c) i.v. injection d) Average dose of 13 × 109 cells per vaccination |
| Zhong et al. (56) | Stage IIIB-IV NSCLC expressing CEA | 28 (14 patients received DC/CIK) | Phase 1/2 | moDCs Immature |
N/A | CEA peptide | a) 4 vaccinations b) 1-month interval c) i.v. injection d) Average dose of 8.1 × 106 cells per vaccination |
| Shi et al. (57) | Stage IIIB-IV NSCLC | 60 (30 patients received DC/CIK) | RCT | moDCs Mature |
GM-CSF TNF IL-6 |
N/A | a) 4-vaccinations b) 1-week interval c) s.c. injection d) Dose not mentioned |
| Yang et al. (58) | Stage IIIB-IV NSCLC | 102 (61 patients received DC/CIK) | Paired cohort study | moDCs Immature |
N/A | Autologous tumor lysate | a) 4 vaccinations b) 1-month interval c) i.v. injection d) Average dose of 12.5 × 109 cells per vaccination |
| Shi et al. (59) | Stage IIIB-IV NSCLC with EGFR exon 19 and/or 21 mutation | 54 (26 patients received DC/CIK) | RCT | moDCs Immature |
N/A | Autologous tumor lysate | a) 8 vaccinations b) 1-week interval c) s.c. injection d) Dose not mentioned |
| Zhao et al. (60) | Resected stage I-III NSCLC (arm 1) or metastatic NSCLC (arm 2) | 50 | Phase 1 | moDCs Mature |
TNF-α | Human A549 or SK-MES-1 lung cancer cell lysate | a) 4 vaccinations b) 1-week interval c) s.c. (DC) and i.v. injection (DC/CIK) d) 1.5 × 107 cells per vaccination |
| Zhu et al. (61) | Stage IIIB NSCLC | 65 (30 received DC/CIK) | RCT | moDCs Mature |
TNF-α | None | a) 4 vaccinations b) 3-week interval c) i.v. injection d) Dose not mentioned |
| Zhang et al. (62) | Stage IIIB-IV NSCLC | 99 | Retrospective analysis | moDCs Immature |
N/A | Human SK-MES-1 and human SPC-A-1 lung cancer cell lysate | a) 6 vaccinations b) 1-week interval c) i.v. injection (first 3 doses) and i.d. injection (last 3 doses) d) 1 × 107 cells per vaccination |
| Zhang et al. (63) | Stage III-IV NSCLC | 82 (21 received DC/CIK) | Phase 2 | moDCs Mature |
TNF-α | MUC1 peptide | a) 4 vaccinations b) 1-week interval c) s.c. injection d) 1 × 107 cells per vaccination |
| Song et al. (64) | Resected stage IIB-IIIA NSCLC | 169 | Phase 2 | moDCs Mature |
N/A | Human A549 or SK-MES-1 lung cancer cell lysate | a) 5 vaccinations within 2 weeks per cycle b) 12-24 week-interval (1–2 cycles) or 4–12 week interval (3–5 cycles) c) i.v. (DC/CIK) and s.c. injection (DC) d) 20 × 106 cells per vaccination |
| Chen et al. (65) | Advanced solid tumors | 37 (5 with NSCLC) | Phase 1 | moDCs Mature |
TNF-α | N/A | a) Median number of 12 vaccinations (range, 3–26) b) 1-week interval for the first 4 doses, then 2-week interval thereafter c) i.v. injection d) Average dose of 8.8 × 109 cells per vaccination |
| AKT-DC therapy in NSCLC | |||||||
| Kimura et al. (66) | Resected stage III-IV NSCLC with N2 disease | 31 | Phase 2 | DCs obtained from tissue cultures of TDLNs Mature |
N/A | N/A | a) Median number of 11 courses (range, 2–18) b) 2-month interval c) i.v. injection d) Mean dose of 7.07 × 109 cells per course e) IL-2 |
| Kimura et al. (67, 68) | Resected stage IB-IV NSCLC | 103 (50 received AKT-DC) | Phase 3 RCT | DCs obtained from tissue cultures of TDLNs Mature |
N/A | N/A | a) Median number of 15 courses b) 1-month interval for the first 6 months, and 2-month interval thereafter c) i.v. injection d) Mean dose of 10, 2 × 109 cells per course |
| DC therapy in SCLC | |||||||
| Chiappori et al. (69) | Extensive disease SCLC | 54 | Phase 1/2 | moDCs Mature |
N/A | p53 viral vector (Ad.p53) |
a) 3 vaccinations and if no PD after reassessment 3 subsequent vaccinations b) 2-week interval for the first 3 vaccinations and 4-week interval for the subsequent 3 vaccinations c) i.d. injection d) Maximum dose of 5 × 106 cells per vaccination |
| Chiappori et al. (70, 71) | Extensive disease SCLC | 69 (51 received DC vaccine) | Phase 2 RCT |
moDCs Mature |
N/A | p53 viral vector (Ad.p53) |
a) 3 vaccinations and if no PD after reassessment 3 subsequent vaccinations b) 2-week interval for the first 3 vaccinations and 4-week interval for the subsequent 3 vaccinations c) i.d. injection d) Average dose of 2–5 × 106 cells per vaccination. |
a) number of vaccinations.
b) dose interval.
c) route of administration.
d) number of DCs injected.
e) adjuvants used.
Ad-CCL21-DC, dendritic cells transduced with an adenoviral vector expressing the CCL21 gene; Ad.p53, dendritic cells transduced with an adenoviral vector expressing p53; anti-PD-1, anti-programmed death-1; CCL21, chemokine ligand 21; CEA, carcinoembryonic antigen; CIK cell, cytokine induced killer cell; CRC, colorectal cancer; DCTCMF, dendritic cell/T cell-derived maturation factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HER-2, human epidermal growth factor receptor 2; HLA, human leucocyte antigen; i.d., intradermal; IL, interleukin; i.n., intranodal; IFN-α, interferon-alpha; IFN-γ, interferon-gamma; i.t., intratumoral; i.v., intravenous; MAGE-1, melanoma-associated antigen-1; MAGE-2, melanoma-associated antigen-2; moDCs, monocyte derived dendritic cells; MUC1, mucin 1; N, number of patients; N/A, not applicable; NSCLC, non-small cell lung cancer; PGE2, prostaglandin E2; RCT, randomized controlled trial; rMAGE-3, recombinant melanoma-associated antigen-3; rSurvvin, recombinant Survivin; s.c., subcutaneous; TDLN, tumor-draining lymph node; TNF-α, tumor necrosis factor-alpha; WT1, wilms tumor protein l.