Table 2.
Clinical and immunological outcomes of dendritic cell (DC)-based immunotherapy in lung cancer.
| Reference | Safety | ORR* | Survival | Immune response | Comments |
|---|---|---|---|---|---|
| DC therapy in NSCLC | |||||
| Fong et al. (35) | Grade 1 or 2 transfusion reaction in 7 patients Grade 1 or 2 diarrhea in 5 patients |
0/2 (0%) | N/A | CEA-specific CD8+ T cell immunity was seen in 7/12 patients (58.3%). | Objective responses were observed in 2 patients, both with CRC. |
| Itoh et al. (36) | Grade 1 local reaction at the injection site in 2 patients | 0/2 (0%) | N/A | A positive response to DTH skin test was seen in 2/10 patients (20%) of which 1 patient with lung cancer. A CEA-specific CTL response was seen in 1/10 patients (10%). | A continuous decrease of serum CEA was observed in 1 patient with lung cancer. Two patients had SD (1 patient with lung cancer). Clinical and immunological responses were only observed in patients treated with adjuvant use of INF-α and TNF-α. |
| Nair et al. (37) | No toxicities | 0/1 (0%) | N/A | A CEA specific and tumor antigen-specific CTL response was seen in the patient with NSCLC. The tumor specific immune response was greater than the CEA specific immune response. | |
| Kontani et al. (38) | Fever in 7 patients | 2/8 (25%) | The MST was significantly longer in MUC positive patients versus MUC negative patients (16.8 vs. 3.8 months; p = 0.0101) | A positive response to DTH skin test was seen in 5/9 patients (55.6%). A MUC1-specific CTL response was seen in 3/7 patients (42.9%). |
Two patients with lung cancer had a PR. The patients who acquired tumor-specific immunity responded to treatment, i.e., reduction in tumor marker levels and disappearance of malignant pleural effusions. |
| Hirschowitz et al. (39, 40) | No serious AEs Grade 1 local reaction at the injection site in 10 patients Grade 1 fatigue in 3 patients |
N/A | N/A | An antigen-specific immune response was seen in 6/16 patients (37.5%). | Favorable and unfavorable clinical outcomes were independent of measured immunologic responses. Five patients had disease recurrence or progression of which 3 patients died of PD. |
| Ueda et al. (41) | No toxicities | 0/5 (0%) | Survival time ranged from 3 to 46+ months with a median of 8 months. | A positive response to DTH skin test was seen in 5/11 patients (45.5%). A CEA-specific CTL response was seen in 6/11 patients (54.5%). | Three of the 5 patients with lung cancer had prolonged and/or marked decreases in serum CEA levels after therapy. |
| Chang et al. (42) | No grade 2 to 4 AEs | 1/8 (12.5%) | N/A | Minor to moderate increases in T cell responses against tumor antigens were observed in 6/8 patients (75%). | Two patients had SD. The 2 patients who had longer disease control also had better T cell responses. |
| Morse et al. (43) | No grade 3 or 4 AEs | 0/3 (0%) | N/A | A CEA-specific immune response among both CD4+ and CD8+ T cells was seen in all evaluable patients (100%). There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or SD. |
One patient had a significant decrease in the CEA level and a minor regression in a retroperitoneal and supraclavicular adenopathy. Five other patients were stable trough at least one cycle of immunization. |
| Hirschowitz et al. (44) | Local reactions at the injection site in most subjects (not specified) | N/A | N/A | A clear immune response was seen in 9/14 patients (64.2%). | Five patients had disease recurrence or progression of which 3 patients died of progressive disease. Three of 5 patients with PD showed no immunological response. |
| Mayordomo et al. (45) | Fever in 6 patients Asthenia in 11 patients |
0/2 (0%) | Survival time ranged from 0 to 29+ months with a median of 7 months. | A positive response to DTH skin test was seen in 9/15 patients (60%) | Seven patients, of which 1 with NSCLC, had SD for > 3 months, and 7 other patients had PD. Time to progression ranged from 0 to 10 months with a median of 3 months. |
| Um et al. (46) | No grade 3 or 4 AEs Grade 1 fever in 1 patient |
0/8 (0%) | N/A | An increase in the percentage of CD8+ cells expressing INF-γ was seen in 5/9 patients (55.6%). | There were mixed responses that fulfill PD definition but demonstrated some clinical benefit in 2 patients. |
| Perroud et al. (47) | Grade 2 fatigue and chills in 1 patient | N/A | Survival time ranged from 82 to 277 days from the last dose of the vaccine with a median of 112 days. | An improvement in the specific immune response after immunization was seen in all patients (100%) but was short lasting. | From the last dose of the vaccine, the time to disease progression ranged between 1 and 82 days. |
| Takahashi et al. (48) | No serious AEs Grade 1 fever in 13 patients Grade 2 fever in 2 patients Grade 1 local reaction at the injection site in 26 patients |
5/62 (8.1%) | MST = 12 months | N/A | Standard chemotherapy regimens were continued in 36 patients during DC vaccination. DCR was seen in 50% of the patients. Better survival was found in patients with ECOG-PS 0 or 1 and in patients who received > 5 vaccinations. |
| Hu et al. (49) | Grade 1 fever in 5 patients | 3/27 (11.1%) | Median OS = 10.5 months Median PFS = 4.5 months |
N/A | |
| Takahashi et al. (50) | N/A | 29/260 (11.2%) | MST = 13,8 months The survival rates from the first vaccination were 53.5% after 1 year, 36.1% after 2 years, and 8.8% after 5 years. |
N/A | 185 (71.4%) patients received DC vaccines combined with simultaneous chemotherapy. Patients with an adenocarcinoma had a significantly better prognosis compared to other subtypes (MST 15.3 months vs. 8.8 months; p = 0.003). An erythema reaction at the injection site that was ≥ 30 mm in diameter was correlated most strongly with OS from the first vaccine (MST 20.4 vs. 8.8 months; p<0.001). |
| Li et al. (51) | No serious AEs Grade 1 temporary exanthema in 1 patient Grade 1 pruritus in 3 patients Grade 1 chills in 1 patient Grade 1 fever in 1 patient Grade 1 fatigue in 1 patient |
0/16 (0%) | Survival rates from DC therapy was mentioned in three patients and ranged from 6 to 12 months. | A positive response to DTH skin test was seen in all patients (100%). There was a significant increase in INF-γ expression on day 60 vs. day 0. There was an increasing trend in the mean CD4:CD8 values between day 30 and day 90. |
5 patients had disease recurrence or progression of which 3 patients died of stage IV NSCLC. |
| Lee et al. (52) | Grade 1 flu-like symptoms in 1 patient Grade 1 hemoptysis after each injection in 1 patient Grade 1 nausea in 1 patient Grade 1 fatigue in 1 patient |
N/A | MST = 3.9 months | A systemic response against TAA’s was seen in 6/16 patients (37.5%). Tumor CD8+T cell infiltration was induced in 54% of subjects. Patients with increased CD8+T cells following vaccination showed significantly increased PD-L1 mRNA expression. |
SD was seen in 25% of patients at day 56 |
| Teramoto et al. (53) | Fever in 16 patients Local reaction at the site in 6 patients Acute lung injury in 1 patient |
0/28 (0%) | MST = 7.4 months | MUC1-specific cytotoxic immune responses were seen in 7/7 patients (100%). | A higher MST was seen in patients receiving > 6 vaccinations, in patients with adverse events, and in patients with higher percentage of peripheral lymphocytes. The DCR in the group of patients that had received 6 vaccinations was 42.9%. |
| Ge et al. (54) | No serious AEs Grade 1–2 fever in 6 patients Grade 1–2 fatigue in 5 patients Grade 1–2 myalgia in 6 patients Grade 1–2 chills in 1 patient |
N/A | N/A | A significant decrease in CD3+ CD4+ CD25+ Foxp3+ T regulatory cell number and increase in TNF-α and IL-6 were seen in 2/15 patients (13.3%). | Two patients showed 15% and 64% decrease in CEA and CYFRA21 respectively. The vaccination with the maximum dose significantly improved QOL when administered at the highest dose. In the low dose group: 1 patient had no recurrence, 1 patient had PD and 1 patient had died In de middle dose group: all 3 patients had no recurrence. In the high dose group: 1 patient had died, 1 patient had PD and 7 patients had no recurrence. |
| DC/CIK therapy in NSCLC | |||||
| Li et al. (55) | No grade 3 or 4 AEs | N/A | The 2-year OS was significantly increased in the immune-CT group comparing to the non-immunotherapy group (p<0.05). | An increased production of cytokines that have known anti-tumor effects was seen, including IFN-γ, TNF-α and TNF-β, in patients who had no progression, but they were not found in patients who developed recurrence. |
The 2-year DFS in the immune-CT group (75.6 ± 7.2%) was higher than that in the CT-group (65.3 ± 8.0%) but there was no significant difference. Immunotherapy was started 1 month after chemotherapy in the chemoimmunotherapy group. |
| Zhong et al. (56) | Grade 1–3 skin toxicity in 9 patients Grade 1–4 fever in 10 patients |
N/A | There was no statistically difference in OS between the chemoimmunotherapy group and chemotherapy group (p = 0.18). | N/A | In the chemoimmunotherapy group, CEA level decreased in 3 patients, and remained stable in 9 patients. The median time to progression in de chemoimmunotherapy group was 6.9 months (95% CI: 5.0-8.8) and 5.2 months (95% CI: 3.3-6.0) in the chemotherapy group (p = 0.03). |
| Shi et al. (57) | Fever in 4 patients | 1/30 (3.3%) | The PFS was significantly increased in the DC/CIK cell group compared to the control group (3.2 vs. 2.56 months; p<0.05). | After treatment, an increase in NK-cells, CD3+ and CD4+ T cells was seen, and a decrease in CD8+ cells. | |
| Yang et al. (58) | No serious AEs | 11/61 (18%) | The 1- and 2-year OS rates were 57.2 and 27% in the chemoimmunotherapy group and were significantly higher than in de chemotherapy group (p<0.05). | A significant increase in the secretion of INF-γ and TNF-α was seen, and a decrease in TGF-β. An enhanced antitumor activity was seen, as well as an increased CD3+CD56+ cell ratio. |
There was no significant difference in the survival rate between the adenocarcinoma and squamous carcinoma patients. |
| Shi et al. (72) | Fever in 3 patients Rash in 14 patients Diarrhea in 9 patients |
N/A | The PFS was significantly longer in the DC/CIK plus erlotinib group compared to the erlotinib group (5.02 vs. 3.98 months; p<0.05). There was no statistically significant difference in median OS between both groups (p = 0.29). |
An increase in the levels of CD3+, CD4+ and CD8+ T cells was found after therapy in the DC/CIK plus erlotinib group, but not in the erlotinib group. | |
| Zhao et al. (60) | N/A | N/A | N/A | The serum concentrations of the Th2 cytokines (IL-4 and IL-10) in tumor-bearing patients were significantly higher than those with resected NSCLC before immunotherapy. The post-therapy Th1 cytokine (INF-γ) level in patients with resected NSCLC significantly increased from the pre-therapy level. In tumor-bearing patients, significantly enhanced post-therapy Th2 cytokine (IL-4 and IL-10) levels were found. |
|
| Zhu et al. (61) | Grade 1-2 fever in 5 patients | 25/30 (83.5%) | 1-year OS was significantly higher in the treatment group than in the control group (83.3% vs. 60.6%; p<0.05). | A significant increase of CD3+, CD4+ and CD4+/CD8+ was seen in the treatment group, but not in the control group. | |
| Zhang et al. (62) | Grade 1-2 fever in 30 patients Grade 3 fever in 6 patients Grade 1-2 skin rash in 7 patients |
N/A | The OS time was significantly increased in comparing to the non-immunotherapy group (p = 0.03). | A positive response to DTH skin test was seen in 59 patients (60.8%). | Matched patients (N = 408) with NSCLC that did not receive DC-CIK acted as the control group. |
| Zhang et al. (63) | Grade 1-2 fever in 5 patients Grade 1-2 anorexia in 3 patients Grade 1-2 nausea in 3 patients Grade 1-2 radiation pneumonitis in 4 patients Grade 3 radiation pneumonitis in 3 patients |
10/21 (47.6%) | The median PFS was significantly longer in the DC/CIK group than in the control group (330 days vs. 233 days; p = 0.0483). There was no difference in median OS between both groups (p = 0.606). |
No difference was seen in the serum levels of IL-2 and INF-γ in the two groups both before and after thoracic radiotherapy. No changes were seen in the levels of CD8+ cells or CD4+ cells. A tendency of a decrease in de CD4+/CD8+ T cell ratio was seen in the control group. |
|
| Song et al. (64) | N/A | N/A | N/A | Decreased levels of circulating Tregs and related immunosuppressive cytokines were seen after increased cycles of DC/CIK treatment. | Recurrence rate was lower in the ≥ 3 cycles group compared to < 3 cycles group (p = 0.022). |
| Chen et al. (65) | Grade 3-4 AEs in 2 patients Grade 1-2 fever in 8 patients Grade 3-4 fever in 1 patients Grade 1-2 chills in 2 patients Grade 3-4 chills in 1 patients |
7/31 (22.5%) | OS = 270 days | PD-L1 expression was induced on autologous tumor cells by tumor-reactive DC-CIK cells and elevated IFN-γ secretion was seen. | Among patients with NSCLC, SD was seen in 1 patient. |
| AKT-DC therapy in NSCLC | |||||
| Kimura et al. (66) | Fever in 78.0% of the courses Chills in 83.4% of the courses Fatigue in 23.0% of the courses Nausea in 17.0% of the courses |
N/A | The 2- and 5-year OS rates were 88.9% and 52.9% respectively. | N/A | The 5-year survival rate of the group that received > 5.0 × 1010 cells was better than the group that received less (80.8% vs. 38,5%). |
| Kimura et al., (67, 68) | Fever in 6.2% of the courses Chills in 6.8% of the courses |
N/A | The 2- and 5-year OS rates were 96.0% and 69.4% in group A and 64.7% and 45.1% in group B, respectively, with a HR of 0.474. | The CD8+/CD4+ T cell ratio was higher in the survivors than in the deceased (p = 0.0013). | A higher OS was seen in patients ≤ 55 years (HR 0.0098), male patients (HR 0.474), patients with adenocarcinoma (HR 0.479), patients with stage III cancer (HR 0.399) and patients who did not receive preoperative chemotherapy (HR 0.0483). |
| DC therapy in SCLC | |||||
| Chiappori et al. (69) | Grade 1 arthralgia and myalgia in 9 patients Grade 2 arthralgia in 1 patient Grade 1 fatigue in 5 patients Grade 2 fatigue in 1 patient Grade 1 local reaction at the injection site in 5 patients Grade 1 injection site pain in 4 patients |
2/54 (3.7%) | The MST from first vaccination was 8.8 months. | A significant p53-specific immune response was seen in 18/43 patients (41.2%). | Patients with a positive immune response had a trend towards improved survival. 78.6% of the patients with a positive immune response had a clinical response to 2nd line chemotherapy compared to 33.3% patients with a negative immune response. |
| Chiappori et al. (70, 71) | Grade 3 fatigue in 1 patient. Grade 3 toxicities in 8 patients receiving vaccine + ATRA |
1/45 (2.2%) | Survival from date of enrollment was numerically higher in arm A (12.2 months), than in arm B (6.3) and arm C (6.2) but not statistically different. | Positive immune responses were obtained in 20% of arm B (vaccine alone) and 43.3% of arm C (vaccine + ATRA). | No difference was seen in OS between patients with a positive immune response and those with a negative immune response (9.2 vs. 9.3 months; p = 0.250). |
*Only responses in lung cancer patients are mentioned.
AE, adverse event; AKT, activated killer T cells; ATRA, all-trans-retinoid acid; CEA, carcinoembryonic antigen; CI, confidence interval; CIK, cytokine induced killer; CRC, colorectal cancer; CT, chemotherapy; CTL, cytotoxic T-lymphocyte; DCR, disease control rate; DFS, disease free survival; DTH, delayed-type hypersensitivity; ECOG-PS, Eastern Cooperative Oncology Group-Performance Status; HR, hazard ratio; IL, interleukin; INF-α, interferon-alpha; INF-γ, interferon-gamma; MST, median survival time; N/A, not available; ORR, objective response rate; OS, overall survival; PD, progression of disease; QOL, quality of life; SD, stable disease; TAA, tumor-associated antigen; TNF-α, tumor necrosis factor-alpha; TGF-β, transforming growth factor-beta.