Abstract
Background
Immuno-cell therapy using activated lymphocytes (ALs) and/or dendritic cells (DCs) is considered one of the less toxic supportive therapies compared with conventional chemotherapy and radiotherapy, especially for the treatment for advanced cancers. To improve the efficacy of immuno-cell therapy for such cancer, clinical data were analyzed in this preliminary study.
Patients and methods
The clinical data of 38 consecutive patients with advanced cancer who underwent at least one course of treatment with ALs and/or matured DCs, with or without antecedent surgery or additional conventional chemotherapy and/or radiotherapy, were evaluated.
Results
Of the 23 patients who received surgery before immuno-cell therapy, 2 (8.7%) showed a complete response (CR) and 15 (65%) showed a partial response (PR) or prolonged stable disease (SD). Of the 15 remaining patients who did not undergo antecedent surgery, there was no CR but 7 (46%) showed PR or prolonged SD. Actuarial survival is one of the important indices for the evaluation of anticancer therapies that present longer durable efficacy of immunotherapy compared with conventional anticancer chemotherapy and radiotherapy, and actuarial survival analysis revealed that immuno-cell therapy with antecedent surgery afforded significantly longer survival than immuno-cell therapy without antecedent surgery (P < 0.001).
Conclusion
Antecedent surgical resection of tumors is advisable for obtaining better efficacy of immuno-cell therapy, even in advanced cancer patients.
Keywords: Immuno-cell therapy, Activated lymphocyte, Dendritic cell vaccination, Immuno-chemotherapy, Advanced cancer
Introduction
Improved immuno-cell therapy using activated lymphocytes (ALs) with or without dendritic cell (DC) vaccination is performed at Mediotopia Numazu Clinic, Japan, as one of the supportive therapies for patients with advanced cancer and refractory cancer. Immuno-cell therapy has very low toxicity and exhibits fewer side effects than conventional chemotherapy and radiotherapy, as has been demonstrated over the past 20 years of clinical trials with immuno-cell therapy, including those conducted for “highly advanced medical technology” in some medical institutions under the approval of the Japanese Ministry of Health, Labor and Welfare.
Currently in Japan, immuno-cell therapy is an accepted and widely used treatment for advanced cancers with or without the use of the three major conventional anticancer therapies of surgery, chemotherapy, and radiotherapy. Immuno-cell therapy is designed to protect the patient’s immune system against tumor cells, but is at present not funded by the national health insurance system.
In this preliminary clinical study, the clinical data for 38 consecutive patients with advanced cancers who were treated with activated lymphocyte therapy (ALT) and/or matured dendritic cell therapy (DCT), with or without antecedent surgery or additional conventional chemotherapy and/or radiotherapy, were analyzed and compared to assess the clinical factors that improve the efficacy of immuno-cell therapy.
Patients and methods
Patients and treatment
Patients with malignant cancer confirmed histologically at antecedent treatment underwent immuno-cell therapy with ALs with or without matured DCs at Meditopia Numazu Clinic between November 2007 and November 2010. Written informed consent was obtained from all patients before the start of immuno-cell therapy.
The clinical data for 38 consecutive patients (18 men, 20 women; mean age, 64 years; age range 39–83 years) were evaluated. The Eastern Cooperative Oncology Group (ECOG) performance status [1] at the beginning of the treatment was PS-0 in 18 patients, PS-1 in 17, PS-2 in 2, and PS-3 in 2. All patients underwent at least one course of treatment consisting of 6 infusions of ALs (3–10 × 109) and/or matured DCs (1–10 × 106) intravenously or subcutaneously at intervals of around 2 weeks. The patients also received additional conventional chemotherapy and/or radiotherapy in combination when indicated. The Seta Clinic Group, which supplies our clinic with ALs and DCs, has performed immuno-cell therapy (i.e., AL therapy (ALT) and matured DC therapy (DCT)) over the past 10 years [2]. The clinics within this group are equipped with a clean room that enables aseptic handling of living cells and can produce a sufficient number of cells for administration to a large number of patients [3]. The cell processing and immuno-cell therapy processing used were approved by the Ethics Committee of the Seta Clinic Group.
The generation and augmentation of ALs and the preparation of tumor lysates and peptides for DC vaccination were performed using lymphocytes and monocytes collected from peripheral blood. The precise processing of these cells is described elsewhere [4–6]. We obtained approximately 22.5 ml of peripheral blood, and mononuclear cells (MNCs) were then separated using Vacutainer (Becton–Dickinson, NJ, USA). MNCs were cultured for 2 weeks with 700 IU/ml recombinant interleukin-2 (Proleukin®, Chiron, Amsterdam, The Netherlands) following activation with immobilized anti-CD3 monoclonal antibody (Jannsen-Kyowa, Tokyo, Japan) using HyMedium 930 (Kohjin Bio, Saitama, Japan) containing 1% autologous serum. After culturing for 14 days, 3–10 × 109cells were harvested and suspended in 100 ml of saline for intravenous injection. To generate DCs, 45 ml of peripheral blood was collected and MNCs were separated. MNCs were then allowed to adhere to the plastic culture flask to obtain adherent cells, which were cultured in the presence of 50 ng/ml GM-CSF (Primmune Corp, Osaka, Japan) for 6 days to generate immature DCs. Twenty-four hours prior to administration, DCs were cultured with appropriate antigens for the tumors and approximately 1–5 × 106 matured DCs were harvested for subcutaneous or intravenous injection. Peptides used for pulsing DCs were purchased from Qiagen (Tokyo, Japan). The types of peptide [7] used and their epitopes and HLA specificities are shown in Table 1.
Table 1.
Antigens used to pulse DCs
| Antigens | HLA specificity | Epitope | Cancers |
|---|---|---|---|
| SART-1 | HLA-A26 | KGSGKMKTE | Various cancers |
| NY-ISO-1 | HLA-A31 | LAAQERRVPR | Melanoma, various cancers |
| MUC-1 (29 mer) | HLA non-restrictive | GVTSAPDTRPAPGSTAPPAHGVTSAPDTR | Pancreas, various cancers |
| MAGE-! | HLA-A24 | NYKHCFPEI | Melanoma, various cancers |
| MAGE-3 | HLA-A24 | TFPDLESEF | Melanoma, various cancers |
Clinical responses and assessment
Clinical response was evaluated by physical and/or radiographic examination as follows: complete response (CR) was defined as the disappearance of all lesions for at least 4 weeks; partial response (PR) as a reduction of more than 50% in the product of the bidimensional diameter for at least 4 weeks; progressive disease (PD) as the appearance of a new lesion or an increase of more than 25% in the product of the bidimensional diameter of an existing lesion; and stable disease (SD) as neither PR nor PD. A prolonged SD was defined as “long SD” that remained unchanged for more than 6 months.
Statistical analysis
Patients were evaluated for demographic, physical, and laboratory variables. The distributions of these variables were compared by the chi-square test for qualitative variables and Fisher’s Student t test for quantitative variables.
The efficacy rate was calculated by taking the percentage of the sum of the number of patients with CR, PR, and long SD with respect to the total number of patients, using the chi-square test. The number of patients with long SD was added to the calculation of efficacy rate, as the effectiveness of immuno-cell therapy takes longer for the effects to show than that of conventional anticancer drugs. Patient survival was analyzed using the Kaplan–Meier method. Differences in survival were determined using the log-rank test for univariate analysis. Statcel ver.2 for Windows Excel statistical software was used for all analyses.
Results
Patient characteristics
Among the 38 patients, the original site of advanced cancer was the lung in 5 (13.2%) patients, liver and bile duct in 4 (10.5%), pancreas in 8 (21%), esophagus in 4 (10.5%), stomach in 4 (10.5%), colon in 1 (2.6%), breast in 3 (7.9%), uterus in 2 (5.2%), ovary in 4 (10.5%), and other sites in 3 (7.9%).
The ECOG performance status at first visit was PS-0 in 17 (44.7%) patients, PS-1 in 17 (44.7%), PS-2 in 2 (5.2%), and PS-3 in 2 (5.2%). All patients tolerated at least one course of the immuno-cell therapy without any toxic side effects from the therapy itself. The disease was stage IV in 19 (50%) patients with distant metastases at various sites and stage III in 19 (50%) patients. Twenty-three (60.5%) of the total 38 patients had previously undergone curative surgery (antecedent surgery group), while the remaining 15 (39.5%) had not undergone surgery but had received chemotherapy and/or radiotherapy (non-antecedent surgery group). In the antecedent surgery group were 7 (36.8%) of the 19 patients with stage IV disease and 16 (84.2%) of the 19 patients with stage III disease. Staging grade was significantly different between the antecedent surgery group and non-antecedent surgery group (P < 0.0034).
Patients in the antecedent curative surgery group presented with recurrence of disease or metastatic lesions at an average of 22.5 months after the primary operation. The time interval between recurrence and the start of immuno-cell therapy was 11.34 and 5.2 months in the antecedent surgery group and non-antecedent surgery group, respectively. During this time interval, the patients received conventional chemotherapy and/or radiotherapy before visiting us to start immuno-cell therapy. The antecedent surgery group took a longer time interval (11.34 months) to receive conventional chemotherapy and/or radiotherapy before immuno-cell therapy than the non-antecedent surgery group (5.2 months). There was a significant difference between the antecedent surgery group and non-antecedent surgery group in the time interval from recurrence to the start of immuno-cell therapy (P < 0.0467). There was, however, no statistical difference between the two groups in terms of the number of infusions of immuno-cell therapy (8.13 vs. 6.33, respectively; P < 0.1580).
Clinical response
ALT alone or in combination with DCT
Of the total 38 patients, 8 (21.1%) were treated with immuno-cell therapy with ALT alone and 10 (26.3%) with ALT + DCT without additional conventional chemotherapy and/or radiotherapy, whereas the remaining 20 (52.6%) patients were treated with ALT in combination with the conventional therapies. All patients received 6 or more infusions of ALs with or without DC vaccinations subcutaneously. The tumor response to therapy was determined after one course of immuno-cell therapy, with a maintenance time of more than 6 months. The results of immuno-cell therapy with or without additional conventional chemotherapy and/or radiotherapy are shown in Table 2.
Table 2.
Response to immuno-cell therapy with or without conventional chemotherapy and/or radiotherapy
| ALT alone | ALT + DCT | ALT + chemotherapy or radiotherapy | Total | P value | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| CR | PR + long SD | SD + PD | CR | PR + long SD | SD + PD | CR | PR + long SD | SD + PD | |||
| Antecedent surgery | 0 | 4 | 1 | 1 | 3 | 3 | 2 | 9 | 0 | 23 | P < 0.01 |
| Non-antecedent surgery | 0 | 0 | 3 | 0 | 2 | 1 | 0 | 5 | 4 | 15 | |
| Total | 8 | 10 | 20 | 38 | |||||||
ALT activated lymphocyte therapy, DCT dendritic cell therapy, CR complete response, PR partial response, long SD prolonged stable disease for more than 6 months, SD stable disease, PD progressive disease
Toxicity was assessed in all patients. Side effects due to immuno-cell therapy were rare, with no treatment-related toxicity apparent in any of the cycles of immuno-cell therapy.
Of the 8 patients treated with ALT alone, 4 (50%) patients achieved long SD, ranging from 7 to 27 months. Two of these patients died 24 months after completion of the therapy. These patients with long SD were all in the antecedent surgery group. There were no cases of CR or PR in the non-antecedent surgery group.
ALT in combination with DCT
Of the 10 patients treated with ALT + DCT (Table 2), 1 (10%) achieved CR and 5 (50%) achieved long SD. One such patient who achieved CR was 1 woman aged 70 years who was diagnosed as having metachronous double cancers in the bilateral lungs and had undergone 4 surgeries over the previous 3 years. Recent newly appeared small-sized lung cancers were treated by molecularly targeted therapy using gefitinib (250 mg per day, orally) [8], but it could not be continued due to severe side effects and this prompted the patient’s referral to us. ALT + DCT combination immunotherapy was started and tumors in the lung disappeared within 3 months and this condition continued for more than 6 months without any signs of recurrence or side effects. At present, she is in good health (PS-0) and can engage in ordinary daily life activities.
Three patients with long SD in the antecedent surgery group survived for 6–16 months, while 2 patients with long SD in the non-antecedent surgery group survived for 11 and 18 months, respectively. All of the long SD patients are surviving to date.
ALT in combination with additional conventional chemotherapy and/or radiotherapy
Of the 20 patients who were treated with combined ALT immuno-cell therapy and additional conventional chemotherapy and/or radiotherapy (Table 2), 2 (10%) achieved CR and 9 (45%) achieved long SD in the antecedent surgery group, and even 5 (55%) of the 9 patients in the non-antecedent surgery group achieved long SD.
As an example case of CR, a female patient aged 48 years with stage III breast cancer underwent curative surgery in May 1996. Two and a half years later, right-sided subclavian lymph node metastasis appeared. This was successfully treated by radiation therapy and disappeared. Since 2004, the patient has received immuno-cell therapy with conventional chemotherapy using trastuzumab and anastrozole [9] at a conventional daily oral dosage. She remains in good health (PS-0) and has been able to work for 84 months since starting immuno-cell therapy.
As another example case, a 67-year-old male patient with stage IIIB lung cancer underwent right upper lobectomy with thoracoplasty in June 2006. He received postoperative chemotherapy using CDDP for 1 year, and 50 Gy irradiation using the fractional method was added the following year for recurrent pleural dissemination. The patient visited our clinic in October 2008 and was treated with immuno-cell therapy. Pleural metastasis disappeared after one course of ALT alone. No further progression was noted for 12 months and he was judged to have achieved CR, although subsequently new lesions appeared in the pleura again. Secondary radiation therapy with 50 Gy using the fractional method for 2 months resulted in pneumonitis and he died from this 2 months later, at 18 months after first receiving immuno-cell therapy.
Nine (81.8%) of the 11 patients who underwent antecedent surgery achieved long SD, ranging from 7 to 32 months. They were all treated with immuno-cell therapy in combination with chemotherapy for various advanced cancers; 3 patients died within 7–17 months after beginning immuno-cell therapy. On the other hand, among 5 (55.5%) of the 9 patients in the non-antecedent surgery group treated with ALT and conventional chemotherapy, only 1 (20%) patient with long SD survived 16 months, although another 4 patients survived more than 6 months but died between 6 and 17 months after the start of the combination therapy.
Comparison of antecedent surgery and non-antecedent surgery group responses
The clinical characteristics of the antecedent surgery group and non-antecedent surgery group were compared statistically and are summarized in Tables 3 and 4. Patients in the antecedent and non-antecedent surgery groups had a variety of different advanced cancers as shown in the Table 3. All patients had advanced cancers of stage III or stage IV. There was no significant difference in age distribution, but there was a significant difference between the two groups in terms of staging grade (P < 0.0034).
Table 3.
Number of primary cancer sites of the antecedent surgery group and non-antecedent surgery group
| Cancer site | Antecedent surgery group | Non-antecedent surgery group |
|---|---|---|
| Lung | 3 | 2 |
| Liver and bile duct | 3 | 1 |
| Pancreas | 2 | 6 |
| Esophagus | 3 | 1 |
| Stomach | 2 | 2 |
| Colon and rectum | 1 | 0 |
| Breast | 3 | 0 |
| Uterus | 2 | 0 |
| Ovary | 3 | 1 |
| Prostatic gland | 0 | 1 |
| Kidney | 1 | 0 |
| Multiple myeloma | 0 | 1 |
| Total | 23 | 15 |
Table 4.
Comparison of clinical data for antecedent surgery group and non-antecedent surgery group
| Antecedent surgery group (n = 23) | Non-antecedent surgery group (n = 15) | P value | |
|---|---|---|---|
| Age (years) | 59.9 (39–81) | 66.7 (65–83) | P < 0.0682 |
| Clinical stage, III versus IV | 17 versus 4 | 3 versus 12 | P < 0.0034 |
| Time interval between recurrence and immuno-cell therapy (months) | 11.34 (1–62) | 5.2 (1–17) | P < 0.0467 |
| No. of infusions (mean) | 8.13 (6–24) | 6.33 (6–13) | P < 0.1580 |
| Efficacy rate: CR + PR + longSD versus SD + PD | 19 versus 4 | 7 versus 8 | P < 0.0092 |
| Actuarial survival rate | Log-rank test P < 0.001 |
ALT activated lymphocyte therapy, DCT dendritic cell therapy, CR complete response, PR partial response, long SD prolonged stable disease for >6 months, SD stable disease, PD progressive disease
The clinical benefits of immuno-cell therapy were estimated statistically by comparing the two groups using the chi-square test: the antecedent surgery group showed a significantly higher response rate (P < 0.0092). This suggests important roles for the antecedent cytoreducing effect of surgery in minimizing tumor extension and preventing dissemination and metastasis of cancer cells to some extent even in patients with advanced cancer in various organs.
Median survival time of the antecedent surgery group and non-antecedent surgery group was 36 and 9 months, respectively. Moreover, analysis of the actuarial survival rate after immuno-cell therapy for the two groups revealed that the antecedent surgery group showed a significantly superior response, as determined by the log-rank test (P < 0.001; Fig. 1).
Fig. 1.
Actuarial Survival Curve of antecedent surgery group (A) and antecedent non-surgery group (B)
In 23 patients in the antecedent surgery group, there was a significantly (P < 0.05) better response in the ALT and chemotherapy combination group (n = 7) than in the ALT + DCT group (n = 11). This finding suggests a certain benefit of immuno-cell therapy using ALs in combination with chemotherapy when planning the appropriate time interval between chemotherapy and immuno-cell therapy in order to prevent direct drug side effects on immuno-cells themselves.
Discussion
Many cytotoxic drugs that have been developed in the past 50 years are widely available for the treatment of advanced cancers. Although they are effective in some types of malignancies such as leukemia, malignant lymphoma, choriocarcinoma, and testicular carcinoma, most other solid and organ tumors such as those in the esophagus, stomach, lung, liver, pancreas, and colon remain refractory to anticancer drugs. Cytotoxic drug therapies inevitably have toxic side effects. The goals of successful cancer therapy should be survival prolongation, symptom palliation, and improved quality of life for patients, especially when designing or evaluating immunotherapy trials because of delayed onset of effects. The high response rate reported for chemotherapy is the result of evaluation based on the temporary reduction in tumor size in accordance with RECIST criteria. However, this has not been shown to clearly correlate with duration of patient survival. Additionally, the tumor-reducing effect of the drug may be short-lived [10, 11]. Under many standard regimens, the median duration of the CR and PR responses is approximately 6 months and less than 12 months at most [12, 13].
Tumor reduction surgery for advanced-staged cancers has been tried widely for more than 10 years and positive results have been obtained with and without perioperative intraperitoneal chemotherapy, especially in the field of ovarian cancer, colorectal cancer, gastric cancer, and other peritoneal cancers [14–16]. However, it has become clear through accumulated clinical experience that in order to improve the clinical benefits afforded by tumor reduction surgery with intraperitoneal chemotherapy, careful selection of patients is needed, and thus, the indication for this technique is strictly limited to a small number of patients with advanced cancer. On the contrary, immuno-cell therapy has almost no toxicity and can be used for patients with various types of cancer and can fundamentally be used with any cancer patients at any clinical stage without additional restrictive criteria for patient selection. Tumor reduction surgery with immuno-cell therapy would therefore be a treatment option that would extend the indications for surgery and is expected to increase the surgical benefits of tumor reduction surgery itself in various kinds of cancers compared with conventional tumor reduction surgery with chemotherapy.
In ALT and/or DCT immuno-cell therapy, no severe side effects were observed and favorable effects were noted in most patients; thus, even in patients with advanced cancer with a low performance status of PS-2 or PS-3 grade, immuno-cell therapy can be tolerated without any side effects. There were 2 (5.2%) patients with PS-2 and 2 (5.2%) with PS-3 who completed at least one course of the immuno-cell trial in this study.
In cases of malignant melanoma, ALT and DCT combination immunotherapy was shown to be superior to ALT alone, with a high tumor response rate and longer duration of response [6], although the present study did not show such a finding. This discrepancy may be due to the wide variety of characteristics of pathophysiological cancer cells in different organs and/or the stage of advanced cancer. A large-scale study is necessary for further evaluation of the efficacy of ALT and DCT combination immunotherapy.
Among the patients in the antecedent surgery group who received immuno-cell therapy, the ALT with chemotherapy subgroup showed a significantly higher response rate than the ALT + DCT subgroup. This may be due to the adjuvant quality of ALT overcoming the profound toxic effects of drug chemotherapy using appropriate time delays between ALT and anticancer drugs to prevent direct drug side effects on activated lymphocytes.
In the present study, antecedent curative surgery before immuno-cell therapy resulted in a favorable outcome, suggesting that antecedent curative surgery is an important factor for obtaining sufficient benefits from immuno-cell therapy through reducing the adverse actions of cancer cells against the patient’s own cells, organs, and their activities. The superiority of immune-cell therapy with antecedent surgery to that with non-antecedent surgery in terms of actuarial survival rate confirmed the total chronological long-term benefits even for patients with advanced cancer.
Recently, molecularly targeted therapy has been developed and extensively used in the treatment of cancer. Its agents directly inhibit receptor activation implicated in the proliferation and survival of cancer cells, resulting in tumor regression, and they are not toxic to lymphocytes. These agents may be used as promising combination therapies; for example, one study found combination therapy using imatinib mesylate in cases of gastrointestinal stromal tumors (GIST) obtained a much higher response rate than imatinib mesylate alone [17], although the number of patients receiving this therapy was small. In our 70-year-old female patient with metachronous bilateral lung cancer, gefitinib therapy was abandoned due to severe drug side effects and she was subsequent treated successfully with ALT + DCT immunotherapy. There is a high potential for the success of treatment with a combination of molecularly targeted therapy and immunotherapy, although the number of reported studies is small [17–19].
In conclusion, although the number of patients treated in this preliminary study was small, statistical analysis clarified that surgery before immuno-cell therapy confers important benefits even for patients with advanced cancer. Such antecedent surgery is advisable in order to obtain higher clinical benefits for such patients in the future. Moreover, detailed indications and criteria for each type of cancer should be examined and decided through large-scale studies.
Acknowledgments
We thank Dr J. Izeki and Dr M. Takagi of Shizuoka General Hospital, Dr K. Chihara of Shizuoka Municipal Hospital and Dr Y. Hirai of Fujieda Heisei Hospital for their valuable support.
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