Utility of cell-based vaccines as cancer therapy: Systematic review and meta-analysis

Figures & data

Figure 1. PRISMA flow diagram.

Figure 2. Quality assessment of the controlled studies.

Table 1. Quality assessment of the single-arm studies.

Study	Item
	1	2	3	4	5	6	7	8	Total score
Lee et al.^Citation13	2	0	2	2	2	2	2	0	12
NemunaitisNemunaitis et al.^Citation14	2	0	2	2	2	2	2	0	12
Powell et al.^Citation15	2	0	2	2	2	2	2	0	12
Avigan et al.^Citation16	2	0	2	2	2	2	2	0	12
Fishman et al.^Citation17	0	2	2	2	2	2	2	0	12
Ribas et al.^Citation18	2	2	2	2	2	2	2	2	16
Oshita et al.^Citation19	0	0	2	2	2	2	2	0	10
Mackiewicz et al.^Citation20	2	0	2	2	2	2	2	2	14
Mackiewicz et al.^Citation20	2	0	2	2	2	2	2	2	14
Chia et al.^Citation21	2	2	2	2	2	2	2	0	14
Creelan et al.^Citation22	2	0	2	2	2	2	2	2	14
Florcken et al.^Citation23	2	0	2	2	2	2	2	0	12
Bapsy et al.^Citation24	2	0	2	2	2	2	2	0	12
Xi et al.^Citation25	0	2	2	2	2	2	2	0	12
Mackiewicz et al.^Citation26	2	0	2	2	2	2	2	2	14
Herbert et al.^Citation27	0	2	2	2	2	2	2	0	12
Percentage of total included studies that are adequate	75	31	100	100	100	100	100	31	6.25

Score: 0- not reported, 1- reported but inadequate, 2- reported and adequate.

Items: 1- A clearly stated aim, 2- Inclusion of consecutive patients, 3- Prospective collection of data, 4- Endpoints appropriate to the aim of the study, 5- Unbiased assessment of the study endpoint, 6- Follow-up period appropriate to the aim of the study, 7- Loss to follow up less than 5%, 8- Prospective calculation of the study size.

Table 2. Characteristics of all studies included in the systematic review.

Characteristic	Type of study		Total; N = 36
	Single arm; N = 16	Controlled; N = 20
Sample Size
Median	29.5	122
Range	8–99	15–689
Age
Range	27–85	19–91
Sex (% Female)
Range	13.6% − 62.3%	10.3% − 52.9%
Clinical setting
Adjuvant	0	16 (80%)	16 (44%)
Advanced/Metastatic	12 (75%)	4 (20%)	16 (44%)
Recurrent	3 (19%)	0	3 (8%)
NA	1 (6%)	0	1 (3%)
Type of cancer
Colon	0	3 (15%)	3 (8%)
Colorectal	0	2 (10%)	2 (6%)
Glioblastoma	0	3 (15%)	3 (8%)
Hepatocellular carcinoma	1 (6%)	2 (10%)	3 (8%)
Malignant glioma	0	1 (5%)	1 (3%)
Melanoma	5 (31%)	5 (25%)	10 (28%)
NSCLC	2 (13%)	1 (5%)	3 (8%)
Prostate Cancer	1 (6%)	2 (10%)	3 (8%)
Renal cell carcinoma	3 (19%)	1 (5%)	4 (11%)
Nasopharyngeal carcinoma	1 (6%)	0	1 (3%)
Malignant mesothelioma	1 (6%)	0	1 (3%)
Multiple	2 (13%)	0	2 (6%)
Type of cellular vaccine
Dendritic cell vaccine	9 (56%)	10 (50%)	19 (53%)
Autologous tumor cell vaccine	2 (13%)	6 (30%)	8 (22%)
Allogeneic tumor cell vaccine	5 (31%)	4 (20%)	9 (25%)
Publication Year
1989	0	1 (5%)	1 (3%)
1993	0	1 (5%)	1 (3%)
1996	0	1 (5%)	1 (3%)
1998	0	1 (5%)	1 (3%)
2000	0	1 (5%)	1 (3%)
2004	0	1 (5%)	1 (3%)
2005	1 (6%)	2 (5%)	3 (8%)
2006	2 (13%)	1 (5%)	3 (8%)
2007	1 (6%)	0	1 (3%)
2008	1 (6%)	0	1 (3%)
2009	0	1 (5%)	1 (3%)
2010	1 (6%)	1 (5%)	2 (6%)
2012	4 (25%)	2 (10%)	6 (17%)
2013	2 (13%)	0	2 (6%)
2014	1 (6%)	2 (10%)	3 (8%)
2015	2 (13%)	1 (5%)	3 (8%)
2016	0	1 (5%)	1 (3%)
2017	0	1 (5%)	1 (3%)
2018	1 (6%)	1 (5%)	2 (6%)
2021	0	1 (5%)	1 (3%)
Length of Follow-up (for Overall Survival)
Less than 5 years	-	9 (45%)	-
Five years or longer	-	11 (55%)	-

Figure 3. Meta-analysis of objective response to cell-based cancer vaccine therapy in single-arm trials, using the response evaluation criteria in solid tumors (RECIST). Figure 3a depicts the findings of the meta-analysis evaluating the disease control rate (DCR) with cell-based cancer vaccines. Figures 3b–e depict the findings of the meta-analysis evaluating the rates of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD), respectively.

Figure 4. Meta-analysis of cell-based cancer vaccine therapy and overall survival (OS). Figure 4a depicts the findings of the meta-analysis evaluating the association between cell-based cancer vaccine therapy and clinical outcome (OS) in the adjuvant setting. Figure 4b depicts the findings of the meta-analysis evaluating the association between cell-based cancer vaccine therapy and clinical outcome (OS) in the advanced/metastatic disease setting. Figure 4c depicts the findings of the meta-analysis evaluating the association between cell-based cancer vaccine therapy and clinical outcome (OS) with ≥ 5-year survival follow-up.

Lee WC, Wang HC, Hung CF, Huang P-F, Lia C-R, Chen M-F. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother. 2005;28(5):496–504. doi:10.1097/01.cji.0000171291.72039.e2.

 PubMed Web of Science ®Google Scholar

Nemunaitis J, Dillman RO, Schwarzenberger PO, Senzer N, Cunningham C, Cutler J, Tong A, Kumar P, Pappen B, Hamilton C. et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non–small-cell lung cancer. J Clin Oncol. 2006;24(29):4721–30. doi:10.1200/JCO.2005.05.5335.

 PubMed Web of Science ®Google Scholar

Powell A, Creaney J, Broomfield S, Van Bruggen I, Robinson B. Recombinant GM-CSF plus autologous tumor cells as a vaccine for patients with mesothelioma. Lung Cancer. 2006;52(2):189–97. doi:10.1016/j.lungcan.2006.01.007.

 PubMed Web of Science ®Google Scholar

Avigan DE, Vasir B, George DJ, Oh WK, Atkins MB, McDermott DF, Kantoff PW, Figlin RA, Vasconcelles MJ, Xu Y. et al. Phase I/II study of vaccination with electrofused allogeneic dendritic cells/autologous tumor-derived cells in patients with stage IV renal cell carcinoma. J Immunother. 2007;30(7):749–761. doi:10.1097/CJI.0b013e3180de4ce8.

 PubMed Web of Science ®Google Scholar

Fishman M, Hunter TB, Soliman H, Thompson P, Dunn M, Smilee R, Farmelo MJ, Noyes DR, Mahany JJ, Lee J-H. et al. Phase II trial of B7-1 (CD-86) transduced, cultured autologous tumor cell vaccine plus subcutaneous interleukin-2 for treatment of stage IV renal cell carcinoma. J Immunother. 2008;31(1):72–80. doi:10.1097/CJI.0b013e31815ba792.

 PubMed Web of Science ®Google Scholar

Ribas A, Camacho LH, Lee SM, Hersh EM, Brown CK, Richards JM, Rodriguez MJ, Prieto VG, Glaspy JA, Oseguera DK. et al. Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma. J Transl Med. 2010;8(1):89. doi:10.1186/1479-5876-8-89.

 PubMedGoogle Scholar

Oshita C, Takikawa M, Kume A, Miyata H, Ashizawa T, Iizuka A, Kiyohara Y, Yoshikawa S, Tanosaki R, Yamazaki N. et al. Dendritic cell-based vaccination in metastatic melanoma patients: phase II clinical trial. Oncol Rep. 2012;28(4):1131–1138. doi:10.3892/or.2012.1956.

 PubMed Web of Science ®Google Scholar

Mackiewicz A, Mackiewicz J, Wysocki PJ, Wiznerowicz M, Kapcinska M, Laciak M, Rose-John S, Izycki D, Burzykowski T, Karczewska-Dzionk A. et al. Long-term survival of high-risk melanoma patients immunized with a hyper-IL-6-modified allogeneic whole-cell vaccine after complete resection. Expert Opin Investig Drugs. 2012;21(6):773–783. doi:10.1517/13543784.2012.684753.

 PubMed Web of Science ®Google Scholar

Chia WK, Wang WW, Teo M, Tai WM, Lim WT, Tan EH, Leong SS, Sun L, Chen JJ, Gottschalk S. et al. A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma. Ann Oncol. 2012;23(4):997–1005. doi:10.1093/annonc/mdr341.

 PubMed Web of Science ®Google Scholar

Creelan BC, Antonia S, Noyes D, Hunter TB, Simon GR, Bepler G, Williams CC, Tanvetyanon T, Haura EB, Schell MJ. et al. Phase II trial of a GM-CSF-producing and CD40L-expressing bystander cell line combined with an allogeneic tumor cell–based vaccine for refractory lung adenocarcinoma. J Immunother. 2013;36(8):442–50. doi:10.1097/CJI.0b013e3182a80237.

 PubMed Web of Science ®Google Scholar

Florcken A, Kopp J, van Lessen A, van Lessen A, Movassaghi K, Takvorian A, Jöhrens K, Möbs M, Schönemann C, Sawitzki B. et al. Allogeneic partially HLA-matched dendritic cells pulsed with autologous tumor cell lysate as a vaccine in metastatic renal cell cancer: a clinical phase I/II study. Hum Vaccin Immunother. 2013;9(6):1217–27. doi:10.4161/hv.24149.

 PubMed Web of Science ®Google Scholar

Bapsy PP, Sharan B, Kumar C, Das RP, Rangarajan B, Jain M, Suresh Attili VS, Subramanian S, Aggarwal S, Srivastava M. et al. Open-label, multi-center, non-randomized, single-arm study to evaluate the safety and efficacy of dendritic cell immunotherapy in patients with refractory solid malignancies, on supportive care. Cytotherapy. 2014;16(2):234–244. doi:10.1016/j.jcyt.2013.11.013.

 PubMed Web of Science ®Google Scholar

Xi HB, Wang GX, Fu B, Liu W-P, Li Y. Survivin and PSMA loaded dendritic cell vaccine for the treatment of prostate cancer. Biol Pharm Bull. 2015;38(6):827–35. doi:10.1248/bpb.b14-00518.

 PubMed Web of Science ®Google Scholar

Mackiewicz J, Karczewska-Dzionk A, Laciak M, Kapcinska M, Wiznerowicz M, Burzykowski T, Zakowska M, Rose-John S, Mackiewicz A. Whole cell therapeutic vaccine modified with hyper-IL6 for combinational treatment of nonresected advanced melanoma. Medicine (Baltimore). 2015;94(21):e853. doi:10.1097/MD.0000000000000853.

 PubMed Web of Science ®Google Scholar

Herbert GS, Vreeland TJ, Clifton GT, Greene JM, Jackson DO, Hardin MO, Hale DF, Berry JS, Nichol P, Yin S. et al. Initial phase I/IIa trial results of an autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine in patients with solid tumors. Vaccine. 2018;36(23):3247–3253. doi:10.1016/j.vaccine.2018.04.078.

 PubMed Web of Science ®Google Scholar