The Future of Cancer Vaccines for Non–Small-Cell Lung Cancer: Ongoing Trials

doi:10.3816/CLC.2008.s.006

Clinical Lung Cancer

Volume 9, Supplement 1, February 2008, Pages S37-S44

https://doi.org/10.3816/CLC.2008.s.006 Get rights and content

Abstract

Lung cancer represents one of the malignancies in which the 3 elements of conventional therapy (ie, surgery, radiotherapy, and chemotherapy) have limited effectiveness in curbing progressive disease. In this context, there is burgeoning interest in the use of vaccine therapy as a nontoxic adjunct to increase the treatment success rates over those obtained with traditional regimens alone. Several clinical trials using a variety of vaccination strategies have been reported or are ongoing. In this review, we have provided an overview of these trials, with a special focus on the clinical efficacy of the vaccines. The future prospects and challenges of vaccine therapy in lung cancer have also been discussed.

References (25)

J Dancey et al.
Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: results of a prospective, randomized phase III trial
Lung Cancer
(2004)
JL Pujol et al.
Survival without common toxicity criteria grade 3/4 toxicity for pemetrexed compared with docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): a risk-benefit analysis
J Thorac Oncol
(2007)
R Feld et al.
Use of the epidermal growth factor receptor inhibitors gefitinib and erlotinib in the treatment of non-small cell lung cancer: a systematic review
J Thorac Oncol
(2006)
NP Restifo et al.
Use of standard criteria for assessment of cancer vaccines
Lancet Oncol
(2005)
B Chan et al.
Adoptive cellular immunotherapy for non-small cell lung cancer: a pilot study
Cytotherapy
(2003)
M Palmer et al.
Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-smallcell lung cancer
Clin Lung Cancer
(2001)
G Gonzalez et al.
Epidermal growth factor-based cancer vaccine for non-small-cell lung cancer therapy
Ann Oncol
(2003)
ME O'Brien et al.
SRL172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer: phase III results
Ann Oncol
(2004)
EA Hirschowitz et al.
Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells
Lung Cancer
(2007)
DM Parkin et al.
Global cancer statistics, 2002
CA Cancer J Clin
(2005)

AB Miller et al.

Reporting results of cancer treatment

Cancer

(1981)

P Therasse et al.

New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada

J Natl Cancer Inst

(2000)

Cited by (21)

Influence of the number and interval of treatment cycles on cytokine-induced killer cells and their adjuvant therapeutic effects in advanced non-small-cell lung cancer (NSCLC)
2017, International Immunopharmacology
Citation Excerpt :
Only 15.9% of patients with lung cancer survive for more than five years after diagnosis [2]. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers [3], and > 50% of patients with advanced local invasion and/or long-distance metastasis, with unresectable treatment, require chemotherapy, radiotherapy, and immunotherapy [4]. Despite the rapid developments in conventional treatment, the prognosis for patients with lung cancer is poor [5].
Cytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).
A total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry.
After in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group (P = 0.0189 and P = 0.0129, respectively). The median OS of the ACT ≥ 4 cycles subgroup was significantly longer than that of the ACT < 4 cycles subgroup (P = 0.0316). The percentage of CIK cells in patients who received ≥ 4 cycles of ACT was higher than that in patients treated with < 4 cycles of ACT (P = 0.0376). Notably, CIK cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells.
Systematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC.
Therapeutic outcomes of combining cryotherapy, chemotherapy and DC-CIK immunotherapy in the treatment of metastatic non-small cell lung cancer
2013, Cryobiology
Citation Excerpt :
Approximately 80% of lung cancers are non-small-cell lung carcinoma (NSCLC) [17] with over 50% of patients with NSCLC exhibiting advanced local invasion and distant metastasis. Some patients with NSCLC are not suitable for surgery, but are suitable for other treatments such as chemotherapy, cryotherapy or immunotherapy [6]. Currently, chemotherapy is the standard treatment for advanced stage and metastatic NSCLC [43]; however, chemotherapy is associated with a decline in sensitivity over time and often has a toxicity profile that reduces quality of life without significantly improving prognosis [41].
Currently there are no effective therapies for the treatment of metastatic non-small cell lung cancer (NSCLC). Here, we conducted a retrospective study of 161 patients to evaluate the therapeutic effects of combining cryosurgery, chemotherapy and dendritic cell-activated cytokine-induced killer cells (DC-CIK) immunotherapy. The overall survival (OS) after diagnosis of metastatic NSCLC to patient death was assessed during a 5-years follow-up period. OS of patients who received comprehensive cryotherapy was (median OS, 20 months; n = 86) significantly longer than that of patients who did not received cryotherapy (median OS, 10 months; n = 75; P < 0.0001). Five treatment combinations were selected: chemotherapy (n = 44); chemo-immunotherapy (n = 31); cryo-chemotherapy (n = 32); cryo-immunotherapy (n = 21); and cryo-chemo-immunotherapy (n = 33). A combination of cryotherapy with either chemotherapy or immunotherapy lead to significantly longer OS (18 months and 17 months, respectively) compared to chemotherapy and chemo-immunotherapy (8.5 months and 12 months, respectively; P < 0.001); however, the median OS of patients who underwent cryo-chemo-immunotherapy was significantly longer (27 months) compared to the other treatment programs (P < 0.001). In conclusion, a combination of cryotherapy, chemotherapy and DC-CIK immunotherapy proved the best treatment option for metastatic NSCLC in this group of patients.
The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: Emphasis on non-small cell lung cancer
2011, Journal of Thoracic Oncology
Citation Excerpt :
The possibly regressing tumors showed a significantly higher number of CD3+ T cells, CD68+ macrophages, and CD57+ NK cells, indicating an immunophenotype resembling that seen in regressing malignant melanomas. During the last decade, because of advances in immunology and molecular biology, the interest in and development of therapeutic tumor vaccines have increased.143,145 This potential treatment modality in NSCLC has moved from using nonspecific immunomodulatory agents to lung cancer-specific tumor antigens and tumor-cell-derived vaccines.146
In addition to malignant neoplastic cells, cancer tissues also include immune cells, fibroblasts, and endothelial cells, including an abundant collection of growth factors, proangiogenic mediators, cytokines, chemokines, and components of the extracellular matrix. The main physiological function of the immune cells is to monitor tissue homeostasis, to protect against invading pathogens, and to eliminate transformed or damaged cells. Between immune cells and malignant cells in the tumor stroma, there is in fact a complex interaction which has significant prognostic relevance as the immune system has both tumor-promoting and -inhibiting roles. In non-small cell lung cancer (NSCLC), there is a marked infiltration of different types of immune cells, and the distribution, tissue localization, and cell types are significantly associated with progression and survival. Cancer immunotherapy has seen a significant progress during the last decade. An increased understanding of the mechanisms by which lung cancer cells escape the immune system, and the recognition of the key tumor antigens and immune system components in tumor ignorance have led to the development of several lung cancer vaccines. As the NSCLC prognosis in general is dismal, one may hope that future immunotherapy may be an effective adjunct to standard therapy, reversing immunologic tolerance in the tumor microenvironment. This review reports on the tumor stroma and in particular tumor-suppressing and -promoting roles of the immune system. Furthermore, it presents recent literature on relevant immune cell-related research in NSCLC.
Molecular biology of lung cancer series
2010, Revue des Maladies Respiratoires
MAGE-A3 est l’acronyme de Melanoma Associated Antigen-A3. Cet antigène est exprimé à la surface des cellules cancéreuses de nombreuses tumeurs mais pas sur les cellules normales à l’exception des cellules germinales testiculaires. Il est présent dans 30 à 60 % des cancers bronchiques non à petites cellules sans que sa fonction ne soit définie. Sa reconnaissance par les lymphocytes T cytotoxiques implique sa présentation à la surface cellulaire par les molécules HLA de type A1 dont les cellules germinales sont dépourvues. Il est donc une cible intéressante pour une immunothérapie anticancéreuse. Les résultats prometteurs des premiers essais de vaccination anticancéreuse avec l’antigène MAGE-A3 ont permis d’obtenir une réponse immunitaire cellulaire avec peut-être un bénéfice en survie. Ils devront être confirmés par des essais randomisés de phase III actuellement en cours en situation adjuvante.
MAGE-A3 (Melanoma Associated Antigen-A3) is expressed in cancer cells but not in normal tissues except male germ line cells which are devoid of Major Histocompatibility Complex molecules and therefore do not present MAGE-A3 antigens.
MAGE-A3 is expressed in 30 to 60% of non-small cell lung cancers but its function is unknown. Its recognition by cytotoxic T lymphocytes implies its presentation on the cell surface by HLA type A1 molecules that are absent from germ cells.
MAGE-A3 represents a good target for active anticancer immunotherapy. Some trials, which used MAGE-A3 and an adjuvant showed a strong antigen-specific T-cell response with, perhaps, an improved survival.
This needs to be confirmed as an adjuvent therapy by current phase III randomized controlled trials.
Active specific immunotherapy and cell-transfer therapy for the treatment of non-small cell lung cancer
2009, Lung Cancer
Citation Excerpt :
An up-to-date understanding of tumor immunology and biology should result in synergistic interactions between treatment arms for the benefit of the patient. The current state-of-the-art is that several promising results in phase I/II studies have encouraged the performance of phase III randomized trials in NSCLC [68]. When these phase III studies are completed within the next couple of years, it is hoped that clinical outcomes supporting acceptance of a substantial role for immunotherapy in the front-line treatment of lung cancer will have been achieved.
Lung cancer is an intractable disease urgently requiring more effective treatment approaches. The potential of immunotherapy in this context remains promising, although presently there are no satisfactory protocols available for lung cancer. However, encouraging evidence of clinical benefits from immunotherapy is beginning to accumulate in several lung cancer trials. Better understanding of tumor-specific immune responses, identifying tumor-associated antigens, and manipulating the immunoregulatory environment of the tumor is likely to further increase the efficacy of immune-mediated cancer therapies. Here, we review recent advances in cellular immunotherapy and vaccines for lung cancer, emphasizing an important paradigm shift in the analysis of clinical benefit away from “tumor response” towards “patient response”.
Dendritic cell-activated cytokine-induced killer cells enhance the anti-tumor effect of chemotherapy on non-small cell lung cancer in patients after surgery
2009, Cytotherapy
Citation Excerpt :
Thus post-operative chemotherapy is a required treatment for patients with lung cancer. Despite current advances in chemotherapy, the prognosis for patients with lung cancer is poor [3,4]. One limitation of current chemotherapy protocols is the lack of clinical evidence of an increase in patients' survival time.
Cytokine-induced killer (CIK) cells have shown cytolytic activity against several tumor cells in vitro and in animal tumor models. Furthermore, CIK cells activated by dendritic cell (DC) stimulation show increased anti-tumor activity. This study aimed to evaluate the clinical efficacy of DC-activated CIK cell treatment following regular chemotherapy and the effects of this therapy on immune responses in patients with non-small cell lung cancer (NSCLC) after surgery.
A paired study, with 42 patients in each group with stage I–IIIa NSCLC after surgery, was performed. Patients received chemotherapy alone (CT) or chemotherapy and DC-activated CIK cell treatment (immuno-CT). Disease-free survival (DFS) and overall survival were evaluated. CIK cell cytotoxicity against tumor cells was detected using a lactate dehydrogenase-based method. Serum cytokine levels in the immuno-CT group were detected using cytokine antibody arrays.
The cytotoxicity of CIK cells was significantly enhanced by DC activation. The 2-year overall survival rate in the immuno-CT group was significantly improved compared with the CT group (94.7 ± 3.6% versus 78.8 ± 7.0%, P < 0.05). The 2-year DFS of these two groups showed no significant difference. DC-activated CIK cell treatment increased production of cytokines that have known anti-tumor effects, including IFN-γ, MIG, TNF-α and TNF-β, in patients who had no progression, but they were not found in patients who developed recurrence/metastasis.
This study suggests that the role of DC-activated CIK cells in improvement of chemotherapy for malignant tumor treatment is associated with up-regulation of the production of cytokines involved in the anti-tumor effect.

View all citing articles on Scopus

Dr Choudhury has no relevant relationships to disclose.

Dr Palma has no relevant relationships to disclose.

Dr Mellstedt has no relevant relationships to disclose.

View full text

The Future of Cancer Vaccines for Non–Small-Cell Lung Cancer: Ongoing Trials

Abstract

Lung Cancer

J Thorac Oncol

J Thorac Oncol

Lancet Oncol

Cytotherapy

Clin Lung Cancer

Ann Oncol