Immunological monitoring of anticancer vaccines in clinical trials

Figures & data

Table 1. Completed Phase III trials for therapeutic cancer vaccines and their inclusion criteria by tumor stage

Development status	Product	Cancer	Tumor stage	Completed phase III	Result	Reference
Approved (US)	Provenge®	Prostate cancer	No	III D9901	F (Efficacy)	^9
			No	III D9902A	F (Efficacy)	^9
			No	III D9902B, IMPACT	S	^10
Approved (Russia)	Oncophage®	Renal cell carcinoma	Stage I, II, III, IV	III C-100–12	F (Efficacy)	^11 ^, ^12
Approved (Switzerland)	M-Vax^TM	Melanoma	Stage IIIb, IIIc	III	NA	^13
Discontinued	Canvaxin®	Melanoma	Stage III	III MMAIT-III	F (Efficacy)	^14
			Stage IV	III MMAIT-IV	F (Efficacy)	^14
Discontinued	PANVAC^TM-VF	Pancreatic cancer	Stage IV	III	F (Efficacy)	^15
Discontinued	Theratope®	Breast cancer	No	III	F (Efficacy)	^16
Discontinued	L-BLP25	Breast cancer	No	III STRIDE	F (Safety)	^17
Discontinued	Specifid^TM	Non-Hodgkin's lymphoma	Grade 1, 2, 3 (WHO)	III	F (Efficacy)	^18
Discontinued	MyVax®	Non-Hodgkin's lymphoma	Stage III, IV	III	F (Efficacy)	^19
Discontinued	GM2-KLH vaccine	Melanoma	Stage IIb, III, IV	III	F (Efficacy)	^20
Discontinued	BEC2	Small cell lung cancer	No	III SILVA	F (Efficacy)	^21
Unknown	Insegia^TM	Pancreatic cancer	No	III (single agent)	S	^22
			Stage II, III, IV	III (combination)	F (Efficacy)	^22
Unknown	OTS-102	Pancreatic cancer	No	II/III PEGASUS-PC	F (Efficacy)	^23
Unknown	Oncophage®	Melanoma	Stage IV	III C-100–21	F (Efficacy)	^24
Ongoing	OncoVAX®	Colorectal cancer	Stage II, III	IIIa 8701	S	^25
Ongoing	Allovectin-7®	Melanoma	Stage III, IV	III (low-dose)	F (Efficacy)	^26
Ongoing	GV1001	Pancreatic cancer	No	III PriomoVax	F (Efficacy)	^27
Ongoing	L-BLP25	Non-small cell lung cancer	Stage IIIa, IIIb	III START	F (Efficacy)	^28
Ongoing	BiovaxID®	Non-Hodgkin's lymphoma	Grade 1, 2, 3a (WHO) / Stage III, IV	III	S	^42 ^- ^44

Table 2. Methods of immune response and clinical outcome evaluation for therapeutic cancer vaccines

Response			Humoral immune response	Cellular immune response						Clinical outcome	Reference
Sample			Peripheral blood lymphocytes					Skin	Tumor lesion
Product	Cancer	Phase	ELISA	ELISPOT	T cell proliferation assay	Intracellular cytokine staining	Flow cytometry	DTH testing	Pathologic assessment
Provenge®	Prostate cancer	P I/II	Y	Y	Y					TTP	^29
		P III (IMPACT)	Y		Y					OS	^10
Canvaxin®	Melanoma (Stage IV)	P II	Y					Y		OS	^30
	Melanoma (Stage II)	P II	Y							DFS	^30
	Melanoma (Stage IIIa, IV)	After P II	Y					Y	Y	OS	^31
Specifid^TM	Non-Hodgkin's lymphoma	P II	Y			Y				OR	^32
		P II (after rituximab)	Y			Y				OR, EFS	^33
BEC2	Small cell lung cancer	P III	Y							OS	^21
		During P III	Y							OS, RFS	^34
Insegia^TM	Pancreatic cancer	P II	Y							OS	^35
		P III (single agent)	Y							OS	^22
M-Vax^TM	Melanoma (Stage III)	Before P III						Y		OS	^36
		P III						Y		OS	^13
MyVax®	Non-Hodgkin's lymphoma	Before P III	Y		Y					PFS	^37
Theratope®	Breast cancer	P II	Y				Y			OS	^38
Total trials			13	1	3	2	1	4	1

Abbreviations: OS, overall survival; TTP, time to progression; DFS, disease free survival; EFS, event free survival; RFS, recurrence free survival; PFS, progression free survival; OR, objective response

Table 3. Evaluation of immune response and clinical outcome after therapeutic cancer vaccines by log-rank test using the Kaplan-Meier model

Product	Cancer	Phase	Evaluation results	Positive Correlation	Reference
Provenge®	Prostate cancer	P I/II	TTP correlated with development of an immune response to prostatic acid phosphatase (PAP) and with the dose of dendritic cells received.	Y	^29
		P III (IMPACT)	An antibody titer of more than 400 against PA2024 or PAP after baseline lived longer than did those who had an antibody titer of 400 or less (p < 0.001 and p = 0.08, respectively). No survival difference could be detected between patients in the sipuleucel-T group who had T-cell proliferation response to PA2024 or PAP and those who did not.	Y	^10
Canvaxin®	Melanoma (Stage IV)	P II	5-y OS rate was 75% for patients who had an elevated level of anti-TA90 IgM and a strong DTH response, 36% for patients who had either an elevated IgM response or a strong DTH response, and only 8% if neither response was strong (p < 0.001)	Y	^30
	Melanoma (Stage II)	P II	Anti-TA90 IgM levels ≧ 1:800 were significantly correlated with improved 5-y DFS and improved 5-y OS.	Y	^30
	Melanoma (Stage IIIa and IV)	After P II	Survival correlated significantly with delayed cutaneous hypersensitiity (p = 0.0066) and antibody response (p = 0.0117).	Y	^31
Specifid^TM	Non-Hodgkin's lymphoma	P II (after rituximab)	There was no correlation observed between the development of anti-Id immune response and the achievement of an objective response or duration of EFS.	N	^33
BEC2	Small cell lung cancer	P III	The survival of responders was better than that of non-responders, although this did not reach statistical significance (median survival, 19.2 v 13.9 mo for responders v non-responders; p = 0.0851).	Y	^21
Insegia^TM	Pancreatic cancer	P II	Median survival was 217 d for the antibody responders and 121 d for the antibody non-responders. The difference in survival between the antibody responders and non-responders was significant (p = 0.0023).	Y	^35
		P III (single agent)	Patients developing anti-G17DT responses (73.8%) survived longer than non-responders or those on placebo (median survival, 176 v 63 v 83 d; log-rank test, p = 0.003).	Y	^40
M-Vax^TM	Melanoma (Stage III)	Before P III	The development of a positive DTH response to unmodified autologous melanoma cells was associated with significantly longer 5-y survival (71% v 49%; p = 0.031).	Y	^36
		P III	OS after relapse was significantly longer in patients who developed positive DTH to unmodified tumor cells (25.2% v 12.3%; p < 0.001).	Y	^13
MyVax®	Non-Hodgkin's lymphoma	Before P III	Patients who mounted humoral immune responses had a longer PFS than those who did not (8.21 v 3.38 y; p = 0.018).	Y	^37
Theratope®	Breast cancer	P II	51 patients who generated titers higher than median value for anti-STn+ mucin IgG survived longer than 46 patients who generated lower titers below the median.	Y	^38

Table 4. Evaluation of immune response and clinical outcome after therapeutic cancer vaccines by Cox proportional hazards model

Product	Cancer	Phase	Evaluation results	Positive association	Reference
Canvaxin®	Melanoma (Stage IV)	P II	Elevated anti-TA90 IgM and strong DTH to vaccine correlated with improved survival (p = 0.03 and 0.008, respectively).	Y	^30
	Melanoma (Stage II)	P II	Anti-TA90 IgM was identified as an independent prognostic factor for OS and DFS.	Y	^30
	Melanoma (Stage IIIa, IV)	After P II	It was revealed prognostic significance for site of metastases (p = 0.0001) and immunotherapy (p = 0.0001).	Y	^31
M-Vax^TM	Melanoma (Stage III)	Before P III	The failure to develop DTH to unmodified autologous melanoma cells was associated with OS (HR = 2.54, p = 0.080). After adjustment for age only, the hazards ratios for RFS and OS increased and were statistically significant (p = 0.029 and 0.036, respectively).	Y	^36
		P III	A positive DTH response to unmodified tumor cells remained statistically significant for both RFS and OS (p = 0.015 and 0.009, respectively).	Y	^13
MyVax®	Non-Hodgkin's lymphoma	Before P III	Valine/valine genotype and humoral immune response were independent positive predictors for PFS (p = 0.0013 and 0.0015, respectively).	Y	^37

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