An Open‐Label Study of the Safety and Efficacy of Tag‐7 Gene‐Modified Tumor Cells‐Based Vaccine in Patients with Locally Advanced or Metastatic Malignant Melanoma or Renal Cell Cancer

Abstract

Lessons Learned

• This study showed that carefully selected patients with locally advanced and metastatic forms of malignant melanoma and renal cell carcinoma could potentially have long‐term disease control with a tag‐7 gene‐modified tumor cells‐based vaccine.

• Randomized clinical trials in patients whose tumors produce low amounts of immunosuppressive factors are needed to confirm this hypothesis in both the adjuvant and metastatic settings.

Background

Immunotherapy may produce long‐lasting effects on survival and toxicity. The magnitude of efficacy may be dependent on immune factors. We analyzed the results of a phase I/II study of a tag‐7 gene‐modified tumor cells‐based vaccine (GMV) in patients with malignant melanoma (MM) or renal cell carcinoma (RCC) with biomarker analysis of immunosuppressive factors (ISFs) production by their tumor cells.

Methods

From 2001 to 2014, 80 patients received GMV: 68 with MM and 12 with RCC. Treatment in the metastatic setting included 61 patients (MM, 51; RCC, 10), and treatment in the adjuvant setting (after complete cytoreduction) included 19 patients (MM, 17; RCC, 2). Twenty‐six patients were stage III (33%), and 54 (67%) were stage IV. The patients’ tumor samples were transferred to culture, transfected with tag‐7 gene, and inactivated by radiation. The produced product was injected subcutaneously every 3 weeks until progression or 2 years of therapy. ISFs were measured in the supernatants of the tumor cell cultures and used as predictive factors.

Results

No major safety issues or grade 5 adverse events (AEs) were seen. One grade 4 and two grade 3 AEs were registered. No AEs were registered in 89.4% of treatment cycles. No delayed AE was found. The 5‐year overall survival (OS) in the intention‐to‐treat population was 25.1%. There were no differences between MM OS and RCC OS (log rank, p = .44). Median OS in the metastatic setting was 0.7 years and in the adjuvant setting was 3.1 years. Classification trees were built on the basis of ISF production (Fig. 1). The median OS was 6.6 years in the favorable prognosis (FP) group (major histocompatibility complex class I polypeptide‐related sequence A [MICA] level ≤582 pg/mL, n = 15) and 4.6 months in the unfavorable (UF) group (MICA level >582 pg/mL, n = 12; p < .0001). No significant differences were found between classification trees based on ISFs (transforming growth factor β1 [TGF‐β1], interleukin‐10 [IL‐10], and vascular endothelial growth factor [VEGF]). In patients with stage III–IV MM with FP, median OS was 2.3 years, with 31% patients alive at 10 years (Fig. 2) in the UF group (0.4 years; log rank, p = 1.94E−5). No FP patients received modern immunotherapy.

Conclusion

GMV showed high results in carefully selected patients with low ISF (TGF‐β1, IL‐10, and VEGF) production. The method should be further investigated in patients with FP.

Discussion

Progress in immunotherapy revealed the possibility of long‐lasting effects of this treatment modality. Previously reported disappointing results were mostly based on the response rate. In the present work, we assessed long‐term survival data and found results for 10‐year survival comparable to those of patients with MM treated with ipilimumab. Despite inferior results for 3‐year OS in the FP group (42%) in comparison with pembrolizumab (45%), nivolumab (52%), and the combination of ipilimumab with nivolumab (58%), distinct mechanism of action, survival results in selected patients, and presence of biomarker for patients selection promote further development of this technology in the contemporary environment.

The presented results demonstrate the importance of creating rigorous criteria for the selection of patients for cellular immunotherapy, taking into account the biological characteristics of malignant tumors. Several aspects of this phenomenon can be used as a source of biomarkers. They can be measured in the blood or locally in the tumor lesion. Owing to the technological features of the method, we can use a new source of biomarkers—the culture of tumor cells that are used for transfection—because no patients could be treated without this step. However, the selection bias is not excluded from our study. On the other hand, ISFs obtained from the primary tumor also has such bias.

Our study showed high negative predictive and prognostic value for vaccine therapy by ISF level production. All patients with increased ISF levels had low OS. It is important to find out when GMV will be futile, rather than to just find patients who will respond to vaccine treatment. There was no absolutely positive predictive and prognostic value. Only a few patients with low ISF levels had good long‐term outcomes. Future trials are essential for the development of this approach.

Figure 1.

Overall survival of vaccine‐based autologous tumor cells modified with the tag‐7 gene, depending on the major histocompatibility complex class I polypeptide‐related sequence A production.

Trial Information

Disease	Melanoma
Disease	Renal cell carcinoma—clear cell
Disease	Renal cell carcinoma—not clear cell
Stage of Disease/Treatment	Metastatic/advanced
Prior Therapy	No designated number of regimens
Type of Study	Phase I/II, cohort study
Primary Endpoint	Toxicity
Primary Endpoint	Overall survival
Secondary Endpoint	Overall response rate
Secondary Endpoint	Correlative endpoint
Additional Details of Endpoints or Study Design
Overall, 80 patients were included across all study cohorts. Common Terminology Criteria for Adverse Events version 3 was used for safety assessment; RECIST 1.1 and immune‐related response criteria systems were used for final efficacy assessment.
The quantitative content of ISFs was measured in the patient's tumor culture supernatants at early passages before transfection. We assay cytotoxic T‐lymphocyte receptor and NK ligand (MICA), TGF‐β1, IL‐10, and VEGF using an enzyme immunoassay in the “sandwich” variant. Results were obtained as factor concentrations and used as continuous variables in the analysis.
Positive outcome by toxicity was considered two or fewer grade 3–4 related AEs in the first 10 patients and less than 10% grade 3–4 AEs in the overall population.
Positive efficacy was considered 30%+ disease control rate or progression‐free survival (PFS) for 6+ months in the metastatic setting or PFS for 12+ months for the adjuvant setting.
In the final biomarker analysis, patients with melanoma were two groups with sufficient effect (SE) and insufficient effect (iSE) for the predictive biomarkers‐based model development. The SE group included those with complete response (CR), partial response (PR), and stable disease (SD) for more than 6 months for the metastatic setting (III and IV inoperable stages) and PFS for more than 12 months for the adjuvant setting (stages III and IV after complete cytoreduction). The group with iSE included those with progression of the disease (PD), SD for less than 6 months in the metastatic setting, and PFS for less than 12 months in the adjuvant setting.
Investigator's Analysis	The primary safety endpoint was met. Showed activity is selected patients by correlative biomarker.

Drug Information: MM Therapeutic

Drug 1
Generic/Working Name	Tag‐7 gene‐modified inactivated tumor cells
Company Name	N.N. Petrov National Medical Research Center of Oncology
Drug Type	Vaccine
Drug Class	Immune therapy
Dose	10,000,000 per flat dose
Route	s.c.
Schedule of Administration	Patients received GMV once in 3 weeks subcutaneously in three points in the paravertebral region. One dose consisted of 10 million transfected and inactivated tumor cells. No dose reduction was allowed.

Dose Escalation: MM Therapeutic

Dose level	Dose of drug: Tag‐7 gene‐modified inactivated tumor cells	No. enrolled	No. evaluable for toxicity
1	10,000,000	47	47

Drug Information: MM Adjuvant

Drug 1
Generic/Working Name	Tag‐7 gene‐modified inactivated tumor cells
Company Name	N.N. Petrov National Medical Research Center of Oncology
Drug Type	Vaccine
Drug Class	Immune therapy
Dose	10,000,000 per flat dose
Route	s.c.
Schedule of Administration	Patients received GMV once in 3 weeks subcutaneously in three points in the paravertebral region. One dose consisted of 10 million transfected and inactivated tumor cells. No dose reduction was allowed.

Dose Escalation: MM Adjuvant

Dose level	Dose of drug: Tag‐7 gene‐modified inactivated tumor cells	No. enrolled	No. evaluable for toxicity
1	10,000,000	21	21

Drug Information: RCC Therapeutic

Drug 1
Generic/Working Name	Tag‐7 gene‐modified inactivated tumor cells
Company Name	N.N. Petrov National Medical Research Center of Oncology
Drug Type	Vaccine
Drug Class	Immune therapy
Dose	10,000,000 per flat dose
Route	s.c.

Dose Escalation: RCC Therapeutic

Dose level	Dose of drug: Tag‐7 gene‐modified inactivated tumor cells	No. enrolled	No. evaluable for toxicity
1	10,000,000	10	9

Drug Information: RCC Adjuvant

Drug 1
Generic/Working Name	Tag‐7 gene‐modified inactivated tumor cells
Company Name	N.N. Petrov National Medical Research Center of Oncology
Drug Type	Vaccine
Drug Class	Immune therapy
Dose	10,000,000 per flat dose
Route	s.c.

Dose Escalation: RCC Adjuvant

Dose level	Dose of drug: Tag‐7 gene‐modified inactivated tumor cells	No. enrolled	No. evaluable for toxicity
1	10,000,000	3	3

Drug Information: Biomarker Finding Cohort

Drug 1
Generic/Working Name	Tag‐7 gene‐modified inactivated tumor cells
Company Name	N.N. Petrov National Medical Research Center of Oncology
Drug Type	Vaccine
Drug Class	Immune therapy
Dose	10,000,000 per flat dose
Route	s.c.

Dose Escalation: Biomarker Finding Cohort

Dose level	Dose of drug: Tag‐7 gene‐modified inactivated tumor cells	No. enrolled	No. evaluable for toxicity
1	10,000,000	27	27

Drug Information: MM Favorable

Drug 1
Generic/Working Name	Tag‐7 gene‐modified inactivated tumor cells
Company Name	N.N. Petrov National Medical Research Center of Oncology
Drug Type	Vaccine
Drug Class	Immune therapy
Dose	10,000,000 per flat dose
Route	s.c.

Dose Escalation: MM Favorable

Dose level	Dose of drug: Tag‐7 gene‐modified inactivated tumor cells	No. enrolled	No. evaluable for toxicity
1	10,000,000	11	12

Drug Information: MM Unfavorable

Drug 1
Generic/Working Name	Tag‐7 gene‐modified inactivated tumor cells
Company Name	N.N. Petrov National Medical Research Center of Oncology
Drug Type	Vaccine
Drug Class	Immune therapy
Dose	10,000,000 per flat dose
Route	s.c.
Schedule of Administration	Patients received GMV once in 3 weeks subcutaneously in three points in the paravertebral region. One dose consisted of 10 million transfected and inactivated tumor cells. No dose reduction was allowed.

Dose Escalation: MM Unfavorable

Dose level	Dose of drug: Tag‐7 gene‐modified inactivated tumor cells	No. enrolled	No. evaluable for toxicity
1	10,000,000	12

Patient Characteristics: MM Therapeutic

Number of Patients, Male	22
Number of Patients, Female	25
Stage	III — 13 IV — 34
Age	Median (range): 47 (23–73)
Number of Prior Systemic Therapies	Median (range): 2 (1–10)
Performance Status: ECOG	0 — 5 1 — 27 2 — 15 3 — 0 Unknown — 0
Other	Metastases localization: lung, 21; liver, 12; lymph nodes, 23; skin, 34; bone, 7
Cancer Types or Histologic Subtypes	Cutaneous melanoma, 46; unknown primary melanoma, 1

Patient Characteristics: MM Adjuvant

Number of Patients, Male	8
Number of Patients, Female	13
Stage	III — 12 IV — 9
Age	Median (range): 47 (21–72)
Number of Prior Systemic Therapies	Median (range): 2 (1–6)
Performance Status: ECOG	0 — 12 1 — 9 2 — 0 3 — 0 Unknown — 0
Other	Metastases localization: lymph nodes, 6; skin, 6
Cancer Types or Histologic Subtypes	Cutaneous melanoma, 21

Patient Characteristics: RCC therapeutic

Number of Patients, Male	8
Number of Patients, Female	1
Stage	IV — 9
Age	Median (range): 49 (25–71)
Number of Prior Systemic Therapies	Median (range): 2 (1–5)
Performance Status: ECOG	0 — 1 1 — 5 2 — 3 3 — 0 Unknown — 0
Other	Metastases localization: lung, 9; liver, 2; lymph nodes, 3; skin, 2; bone, 3
Cancer Types or Histologic Subtypes	Renal cell clear cell cancer, 9

Patient Characteristics: RCC Adjuvant

Number of Patients, Male	0
Number of Patients, Female	3
Stage	IV — 9
Age	Median (range): 57 (44–65)
Number of Prior Systemic Therapies	Median (range): 2 (1–3)
Performance Status: ECOG	0 — 2 1 — 1 2 — 0 3 — 0 Unknown — 0
Other	Metastases localization: lung, 9; liver, 2; lymph nodes, 3; skin, 2; bone, 3
Cancer Types or Histologic Subtypes	Renal cell cancer, 3

Patient Characteristics: Biomarker Finding Cohort

Number of Patients, Male	12
Number of Patients, Female	15
Stage	III — 11 IV — 14
Age	Median (range): 52 (21–73)
Number of Prior Systemic Therapies	Median (range): 2 (0–10)
Performance Status: ECOG	0 — 6 1 — 13 2 — 8 3 — 0 Unknown — 0
Other	This cohort was composed of patients from four primary cohorts (MM adjuvant and therapeutic, RCC adjuvant and therapeutic) with known ISF production in cultures.
Cancer Types or Histologic Subtypes	Cutaneous melanoma, 23 Renal cell cancer, 4

Patient Characteristics: MM Favorable

Number of Patients, Male	3
Number of Patients, Female	8
Stage	III — 6 IV — 5
Age	Median (range): 53 (31–67)
Number of Prior Systemic Therapies	Median (range): 2 (1–10)
Performance Status: ECOG	0 — 4 1 — 6 2 — 1 3 — 0 Unknown — 0
Other	This cohort was composed of patients from four primary cohorts (MM adjuvant and therapeutic) with low or medium MICA production (MICA <582 pg/mL)
Cancer Types or Histologic Subtypes	Cutaneous melanoma, 10; unknown primary melanoma, 1

Patient Characteristics: MM Unfavorable

Number of Patients, Male	7
Number of Patients, Female	5
Stage	III — 5 IV — 7
Age	Median (range): 48.5 (21–73)
Number of Prior Systemic Therapies	Median (range): 2 (1–10)
Performance Status: ECOG	0 — 3 1 — 7 2 — 2 3 — 0 Unknown — 0
Other	This cohort was composed of patients from four primary cohorts (MM adjuvant and therapeutic) with high MICA production (MICA >582 pg/ml)
Cancer Types or Histologic Subtypes	Cutaneous melanoma, 13

Patient Characteristics: Control

Number of Patients, Male	20
Number of Patients, Female	25
Stage	III — 14 IV — 31
Age	Median (range): 47 (27–72)
Number of Prior Systemic Therapies	Median (range): 2 (1–8)
Performance Status: ECOG	0 — 10 1 — 26 2 — 9 3 — 0 Unknown — 0
Other	This cohort was composed of patients from the two primary cohorts (15 from MM adjuvant and 30 from MM therapeutic) with unknown status of MICA production.

Primary Assessment Method: MM Therapeutic

Title	Efficacy
Number of Patients Screened	50
Number of Patients Enrolled	47
Number of Patients Evaluable for Toxicity	47
Number of Patients Evaluated for Efficacy	45
Evaluation Method	RECIST 1.1
Response Assessment CR	n = 0 (0%)
Response Assessment PR	n =1 (2.1%)
Response Assessment SD	n = 5 (10.6%)
Response Assessment PD	n = 39 (83%)
Response Assessment OTHER	n = 2 (4.3%)
(Median) Duration Assessments TTP	69 days, CI: 48–89
(Median) Duration Assessments OS	175 days, CI: 38–311
Outcome Notes	1Y OS — 32% 2Y OS — 22% 3Y OS — 7% 5Y OS — 7% 10Y OS — 7%

Primary Assessment Method: MM Adjuvant

Title	Survival
Number of Patients Screened	25
Number of Patients Enrolled	21
Number of Patients Evaluable for Toxicity	21
Number of Patients Evaluated for Efficacy	21
Evaluation Method	RECIST 1.1
Response Assessment CR	Not applicable
Response Assessment PR	Not applicable
Response Assessment SD	Not applicable
Response Assessment PD	Not applicable
Response Assessment OTHER	n = 21 (100%)
(Median) Duration Assessments TTP	258 days, CI: 0–847
(Median) Duration Assessments OS	‐
Outcome Notes	Median OS was not reached 1Y OS — 73% 2Y OS — 66% 3Y OS — 53% 5Y OS — 53% 10Y OS — 53%

Secondary Assessment Method: MM Adjuvant

Efficacy in unfavorable prognosis melanoma

Primary Assessment Method for Phase I RCC Therapeutic

Title	Efficacy
Number of Patients Screened	12
Number of Patients Enrolled	9
Number of Patients Evaluable for Toxicity	9
Number of Patients Evaluated for Efficacy	9
Evaluation Method	RECIST 1.1
Response Assessment CR	n = 0 (0%)
Response Assessment PR	n = 2 (22.2%)
Response Assessment SD	n = 0 (0%)
Response Assessment PD	n = 7 (77.8%)
Response Assessment OTHER	n = 0 (0%)
(Median) Duration Assessments TTP	114 days, CI: 0–257
(Median) Duration Assessments OS	631 days, CI: 0–1,504
Outcome Notes	1Y OS — 50% 2Y OS — 33% 3Y OS — 33% 5Y OS — 33% 10Y OS — 0%

Primary Assessment Method: RCC Adjuvant

Title	Efficacy
Number of Patients Screened	3
Number of Patients Enrolled	3
Number of Patients Evaluable for Toxicity	3
Number of Patients Evaluated for Efficacy	3
Evaluation Method	RECIST 1.1
Response Assessment CR	Not applicable
Response Assessment PR	Not applicable
Response Assessment SD	Not applicable
Response Assessment PD	Not applicable
Response Assessment OTHER	n = 3 (100%)
(Median) Duration Assessments TTP	365 days, CI: 64–665
(Median) Duration Assessments OS	1,009 days
Outcome Notes	1Y OS — 50% 2Y OS — 33% 3Y OS — 33% 5Y OS — 33% 10Y OS — 0%

Primary Assessment Method: Biomarker Finding Cohort

Title	Efficacy
Number of Patients Screened	80
Number of Patients Enrolled	27
Number of Patients Evaluable for Toxicity	27
Number of Patients Evaluated for Efficacy	27
Evaluation Method	RECIST 1.1
Response Assessment CR	n = 0 (0%)
Response Assessment PR	n = 3 (11.1%)
Response Assessment SD	n = 7 (25.9%)
Response Assessment PD	n = 12 (44.4%)
Response Assessment OTHER	n = 5 (18.5%)
(Median) Duration Assessments TTP	170 days, CI: 87–253
(Median) Duration Assessments OS	455 days, CI: 0–999
Outcome Notes	1Y OS — 51% 2Y OS — 36% 3Y OS — 18% 5Y OS — 18% 10Y OS — 18%

Primary Assessment Method: MM Favorable

Title	Efficacy
Number of Patients Evaluable for Toxicity	11
Number of Patients Evaluated for Efficacy	11
Evaluation Method	RECIST 1.1
Response Assessment CR	n = 0 (0%)
Response Assessment PR	n = 1 (9%)
Response Assessment SD	n = 5 (45%)
Response Assessment PD	n = 3 (27%)
Response Assessment OTHER	n = 2 (18%)
(Median) Duration Assessments TTP	178 days, CI: 50–306
(Median) Duration Assessments OS	865 days, CI: 763–966
Outcome Notes	1Y OS — 100% 2Y OS — 67% 3Y OS — 40% 5Y OS — 40% 10Y OS — 40%

Primary Assessment Method: MM Unfavorable

Title	Efficacy
Number of Patients Evaluable for Toxicity	12
Number of Patients Evaluated for Efficacy	12
Evaluation Method	RECIST 1.1
Response Assessment CR	n = 0 (0%)
Response Assessment PR	n = 0 (0%)
Response Assessment SD	n = 1
Response Assessment PD	n = 9
Response Assessment OTHER	n = 2
(Median) Duration Assessments TTP	62 days, CI: 38–86
(Median) Duration Assessments OS	140 days, CI: 120–160
Outcome Notes	1Y OS — 8% 2Y OS — 8% 3Y OS — 0%

Primary Assessment Method: Phase I Control

Title	Efficacy
Number of Patients Evaluable for Toxicity	12
Number of Patients Evaluated for Efficacy	12
Evaluation Method	RECIST 1.1
Response Assessment CR	n = 0 (0%)
Response Assessment PR	n = 0 (0%)
Response Assessment SD	n = 1
Response Assessment PD	n = 9
Response Assessment OTHER	n = 2
(Median) Duration Assessments TTP	62 days, CI: 38–86
(Median) Duration Assessments OS	140 days, CI: 120–160
Outcome Notes	1Y OS — 32% 2Y OS — 22% 3Y OS — 7% 5Y OS — 7% 10Y OS — 7%

Adverse Events: MM Therapeutic

All Dose Levels, All Cycles
Name	NC/NA	1	2	3	4	5	All grades
Hemoglobin	100%	0%	0%	0%	0%	0%	0%
Pain ‐ arthralgia	100%	0%	0%	0%	0%	0%	0%
Rash: erythema multiforme (e.g., Stevens‐Johnson syndrome, toxic epidermal necrolysis)	99%	0%	1%	0%	0%	0%	1%
Fatigue (asthenia, lethargy, malaise)	99%	1%	0%	0%	0%	0%	1%
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 × 10e9/L)	92%	6%	2%	0%	0%	0%	8%
Flu‐like syndrome	99%	1%	0%	0%	0%	0%	1%
Injection site reaction/extravasation changes	100%	0%	0%	0%	0%	0%	0%
Blood/bone marrow ‐ leukocytosis	100%	0%	0%	0%	0%	0%	0%
Pain ‐ myalgia	99%	1%	0%	0%	0%	0%	1%
Nausea	99%	1%	0%	0%	0%	0%	1%
Pruritus/itching	99%	0%	0%	1%	0%	0%	1%
Rash/desquamation	98%	1%	0%	1%	0%	0%	2%
Dermatology/skin ‐ vitiligo	100%	0%	0%	0%	0%	0%	0%
Edema: trunk/genital	100%	0%	0%	0%	0%	0%	0%

Abbreviations: ANC, absolute neutrophil count; NC/NA, no change from baseline/no adverse event.

Dose‐Limiting Toxicities for Phase I MM Therapeutic

Dose level	No. enrolled	No. evaluable for toxicity	No. with a dose‐limiting toxicity
1	51	51	1

Adverse Events: MM Adjuvant

All Cycles
Name	NC/NA	1	2	3	4	5	All grades
Chills	99%	1%	0%	0%	0%	0%	1%
Fatigue	99%	1%	0%	0%	0%	0%	1%
Fever	99%	1%	0%	0%	0%	0%	1%
Hypotension	99%	0%	0%	1%	0%	0%	1%
Pruritus	99%	1%	0%	0%	0%	0%	1%
Rash/desquamation	99%	0%	1%	0%	0%	0%	1%

Abbreviation: NC/NA, no change from baseline/no adverse event.

Dose‐Limiting Toxicities: MM Adjuvant

Dose level	No. enrolled	No. evaluable for toxicity	No. with a dose‐limiting toxicity
1	17	17	0

Adverse Events: RCC Therapeutic

All Cycles
Name	NC/NA	1	2	3	4	5	All grades
Fever	98%	2%	0%	0%	0%	0%	2%

Abbreviation: NC/NA, no change from baseline/no adverse event.

Dose‐Limiting Toxicities for Phase I RCC Therapeutic

Dose level	No. enrolled	No. evaluable for toxicity	No. with a dose‐limiting toxicity
1	9	9	0

Adverse Events: RCC Adjuvant

No adverse events in 50 cycles

Dose‐Limiting Toxicities for Phase I RCC Adjuvant

Dose level	No. enrolled	No. evaluable for toxicity	No. with a dose‐limiting toxicity
1	3	3	0

Assessment, Analysis, and Discussion

Completion	Study completed
Investigator's Assessment	Primary safety endpoint met. Showed activity is selected patients by correlative biomarker

Significant progress has been made in the development of new methods of systemic therapy for patients with malignant melanoma (MM) and renal cell carcinoma (RCC) in recent years. Many drugs came to clinical practice recently. At the time of study conduction, there was no possibility for the patients to receive them. So, presented data lack positive effect from effective subsequent therapy.

Checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) have proved to be effective in the treatment of advanced and metastatic MM. At the moment, there are no data on the 10‐year overall survival (OS) rate with the use of these drugs, except ipilimumab (10‐year OS rate was 17%). The use of a vaccine based on tumor cells modified with the tag‐7 gene (GMV) in the general population of patients with MM (68 patients) showed a similar result at the same time interval (10‐year OS: 22%). Moreover, in patients with stage III and IV MM in the favorable prognosis (FP) group according to the major histocompatibility complex class I polypeptide‐related sequence A (MICA) concentration with tag‐7 therapy 10‐year OS was 42%, which is significantly higher than with ipilimumab (17%). Of course, the 3‐year OS FP group by MICA (42%) is inferior to the results of pembrolizumab (45%), nivolumab (52%), and the combination of ipilimumab with nivolumab (58%) for the same period. However, according to 5‐year OS, the results were almost equal (42%) compared with pembrolizumab (43%). We postulate that the gene‐modified vaccine has a different mode of action and could be used to induce immune response rather than unblock it. Combinational or sequential strategies could be the most effective in the clinic. Nevertheless, promising survival results in selected patients, and the existence of a biomarker for deciding which patients to treat, will promote further development of this technology in the contemporary environment.

Rosenberg et al. (2004) used World Health Organization (WHO) criteria to describe an objective response rate for vaccines studies. In his work, only 14 (2.6%) out of 440 patients had an objective response—11 partial responses and 3 complete responses. Nowadays, we know that there is a group of patients with progression of the disease (PD) by WHO criteria who have better survival rates on immunotherapy. These results were observed in approximately 30% of patients. In our study, we found 5% of patients with different responses—2 patients with PD by RECIST later had stable disease (SD) by immune‐related response criteria (irRC), and conversely, one patient has SD by RECIST and PD by irRC. Our data represent a similar incidence of this phenomenon. We can propose that the optimal algorithm of efficacy assessment for immunotherapy, including vaccines, should be developed in future trials.

The presented results demonstrate the importance of creating rigorous criteria for the selection of patients for cellular immunotherapy, taking into account the biological characteristics of malignant tumors. These criteria include neutrophil‐to‐lymphocyte ratio, the monocyte‐to‐lymphocyte ratio, the platelet‐to‐lymphocyte ratio, and programmed death‐ligand 1 (PD‐L1) expression, which showed their predictive and prognostic value. However, there are still concerns about the methodological use of leukocyte factors, and no consensus about the standard threshold of PD‐L1 expression for anti‐programmed cell death protein 1 therapy selection has yet been reached.

Immune escape is a well‐known mechanism for resistance to immunotherapy. Several aspects of this phenomenon can be used as a source of biomarkers. They all can be measured in the blood or locally in the tumor lesion. Each source has its advantages and limitations. Owing to the technological features of the method, we can use a new source of biomarkers—the culture of tumor cells that are used for transfection—because no patients could be treated without this step. However, the selection bias is not excluded when using this approach, because not all tumors could be successfully cultured. On the other hand, immunosuppressive factors (ISFs) obtaining from the primary tumor or peripheral blood also has its own bias.

Our study showed high negative predictive and prognostic value for vaccine therapy by ISF level production. All patients with increased ISF levels had low OS. It is equally important to find out when GMV will be futile as it is to just find patients who will respond to vaccine treatment. However, there was no positive predictive and prognostic value. Only a few patients with low ISF levels had excellent long‐term outcomes.

The immunologically tolerant tumor microenvironment has several mechanisms of resistance. High ISF production, such as MICA, transforming growth factor β1, interleukin‐10, and vascular endothelium growth factor, can be one of them. Both local and systemic levels could be involved. We can propose three scenarios of their actions. The first one is antigen presentation impairment at the injection site. In this scenario, high ISF production by vaccine cells prevents effective induction of immune response. The second one is the same mechanisms in tumor lesions that preclude activated immune cells from actions. The third one is systemic immunosuppression caused by these factors. Yet this mechanism is less possible because we do not see major clinical signs of immunosuppression in these patients. Today, we cannot confirm the exact reason for the inefficacy of vaccines. Future biomarker trials will help to understand it. This can also be used for the combination approaches planning.

Our study demonstrated that carefully selected patients with locally advanced and metastatic forms of MM and RCC could potentially have long‐term disease control with GMV. Randomized clinical trials in patients whose tumors produce low amounts of ISF are highly needed to confirm this hypothesis in both the adjuvant and metastatic settings.

Disclosures

The authors indicated no financial relationships.

Figure

Figure 2.

Graphic expression of the quantitative content of immunosuppressive factors in the supernatants of cultures of tumor cells of patients with sufficient and insufficient clinical effect.

Abbreviations: IL‐10, interleukin‐10; MICA, major histocompatibility complex class I polypeptide‐related sequence A; TGF, transforming growth factor; VEGF, vascular endothelium growth factor.