Melanoma

The inducing course of immunotherapy consists of 10 subcutaneous vaccinations (five at weekly and five at fortnight intervals) and takes about 3 months. The supporting vaccination schedule is determined by both a disease stage and a health state of a patient. The treatment is conducted on an outpatient basis.

The vaccine-induced, immune processes destroy the tumor cells and suppress the development of residual disease.

Xenogenic polyantigenic vaccine (XPV) is sterile.

The development of an influenza-like syndrome in the form of a body temperature rise up to 38°, but also and musculoskeletal discomfort are possible. Those symptoms are usually self-limited. The immunotherapy has no side effects attributable to chemoradiotherapy.

XENOVACCINOTHERAPY FOR MELANOMA

Therapeutic vaccination is a strategy that uses tumor-associated antigens to induce tumor-specific, immune responses. The xenogenic (murine) polyantigenic vaccine (XPV) -in which there are main families of common tumor associated antigens - has been developed in the Institute of Clinical immunology. The small structural distinctions of xenogenic tumor-associated antigens from their human analogues render these antigens highly immunogenic and capable of stimulating immune-mediated, antitumor responses in a patient not only at early, but also at late stages of a disease, when tumor-derived immunosuppression is significant for more information.

Surgical resection of the early-stage localized disease is the only curative treatment for malignant melanoma. Metastatic melanoma is usually resistant to the standard cytotoxic therapy, including highly toxic combinations. Hence, immunotherapy has become the mainstay of treatment in advanced melanoma.

Хenovaccinotherapy is able to provide the regress of visceral metastasizes in melanoma patients. The magnetic resonance imaging (MRI) scans shown in Figure 1 indicate disappearance of melanoma metastases in the liver of a patient at 6 months after treatment initiation. This patient achieved a complete long-term remission (follow-up time is of 5 years).

Figure 1. MRI scan of patient P before (A) and at 6 months (B) after vaccinotherapy initiation. The metastatic lesions are indicated by pointers.

With xenovaccinotherapy, connective tissue cysts may be formed in the sites of the former visceral metastasizes, as determined by ultrasound investigations (UI). Focal pneumosclerosis in the sites of the former pulmonary metastatic lesions can be seen on X-ray photograph (see Figure 2).

Figure 2. CT scan of patient K. The site of pneumosclerosis is indicated.

We evaluated the overall 3-year survival in 32 XPV-treated patients with stage VI disease. Their characteristics are presented in Table 1. All patients had measurable or evaluable disease. The control group was composed retrospectively of the patients who received conventional therapy. Each control patient was randomly selected to be a clinically comparable counterpart of a trial patient, so that control and trial groups were evenly balanced by both prognostic and clinical parameters. Throughout the follow-up period the trial patients received no other systemic therapy other than immunotherapy. If it was reasonable and possible, both trial and control patients underwent cytoreductive palliative surgery.

Table 1. Characteristics of the patients assessable for survival.

Characteristic	Trial	Control
Number of patients	32	32
Males/females	10/22	10/22
Age, years (median, range)	48.8 (18-69)	48.2 (24-77)
Site of metastases:
Lymph node, skin/soft tissue	23 (70%)	26 (81%)
Lung	10 (31%)	6 (19%)
Liver	7 (22%)	7 (22%)
Other organs	7 (21%)	8 (25%)
Prior treatment:
Surgery	17 (53%)	16 (50%)
Surgery + chemotherapy	9 (28%)	10 (31%)
Surgery + immunotherapy (IFN)	0 (0%)	1 (3%)
Surgery + chemotherapy + immunotherapy (IFN)	2 (6%)	2 (6%)
Surgery + chemotherapy + physiotherapy	2 (6%)	0 (0%)
Surgery + chemotherapy + radiotherapy	1 (3%)	0 (0%)
no treatment	1 (3%)	3 (9%)

The results obtained point out that the XPV-based therapy is safe for clinical use and has much less toxicity than current standard therapy for melanoma. Noteworthy is that the vaccine-treated patients exhibited no evidence of systemic autoimmune disorders, of which development could not be excluded initially because of the broad range of different antigens present in XPV.

As shown in Figure 3, the median survival of the XPV-treated patients was significantly longer (P < 0.05) than that of the control patients. The overall 3-year survival rate in XPV-treated and control patients was 25% and 2%, respectively. A clinical effect of various grades with a duration not shorter than 6 months was observed in 21 (66%) of the 32 trial patients: complete response, partial response and disease stabilization was achieved in 5 (16%), 2 (6%) and 14 (44%) patients, respectively. Thus, xenovaccinotherapy is capable of prolonging markedly the lifetime in a significant proportion of advanced melanoma patients.

Figure 3. Survival of the XPV-treated and control patients.

Of great importance is that nearly all XPV-vaccinated patients, who was alive 3 years after entry into the study, survived for 2 more years and longer. According our own data, overall 5- year overall survival rate of 51 XPV – treated patients with IV stage disease was nearly 20%. It should be noted that vaccine-treated in this study were the patients with very advanced disease. Their majority had initially unresectable metastases. It is reasonable to believe that the xenovaccinotherapy should be much more effective, if it is started as early as before or immediately after surgical resection of primary tumor and its regional metastases. Consistent with this postulate are our own data illustrating the survival of surgically-treated, III stage melanoma patients. As can be seen in Figure 4, the 6- year survival of XPV-vaccinated patients was much better to that of control patients.

Figure 4. Survival of the trial and control patients with III stage of the disease.

Thus, the results suggest that xenovaccinotherapy may be effectively applied for prophylaxis of melanoma relapse in the surgically treated patients. Since this treatment has no serious side effects, its application appears to be advisable in melanoma patients with not only III , but also II or I stage of the disease.

The cases of applying xenovaccinotherapy for metastatic melanoma are described below.

A 25 year-old female patient P ( a history № 1005) applied to the patient care institution for reason of ulceration of the nevus pigmentosis located in the region of thorax in October, 2000. She was operated. A histologic diagnosis was epithelioid cell melanoma (III stage of Klark invasion; penetration depth — 2 мм). In December 2000 UI revealed enlargement of axillary lymph nodes (until 15 mm) on the left. In February 2001 the affected lymph nodes were surgically ablated. Histologic analysis of the operational material revealed melanoma cells. In April 2001 MRI revealed multiple lesions (until 18 mm) and enlarged lymph nodes in the mediastinum. General controlled hyperthermia ( 43,30 С) was conducted in April 2001 г . The second hyperthermia was performed in May 2001. In June 2001 MRI revealed that the lesions in both the liver and the mediastinum remained and had a tendency to enlarge. Vaccinotherapy was started in in July 2001. At that time the patient complained of marked general weakness. Relative lymphocytosis (41%) was noted. in the blood test. A rise in the body temperature to 38 0 С was registered during a day after each vaccination. Within 24 h post-injection the induration at a rate of about 15 sm developed in the site of injection. In October 2001 MRI revealed no signs of metastatic lesions in the liver. The remission lasted for the following 11 months. At the end of this time period the lymph nodes in the mediastinum decreased in their sizes to normal rate. Disease progression in the form of appearance of multiple subcutaneous lesions in the region of mammary glands and of the left upper arm was noted in August 2002. All metastatic lesions were surgically ablated and vaccinotherapy was further intensified . The following remission lasted for 10 months. In July 2003 subcutaneous lesions were revealed in the lumbar region on the right. Those lesions were surgically ablated. The complex (surgery + vaccinotherapy) treatment ultimately provided a complete long-term remission. In the final analysis, at 3.5 years after vaccinotherapy initiation the patient was in good condition, exhibited no signs of disease.

A 69 year- old female patient G ( a history № 1005) was diagnosed with melanoma of skin on the right foot in January 2000. Metastatic lesions were detected in inguinal lymph nodes. Moreover, UI revealed multiple focal lesions of 5—6 mm diameter within the right lobe of the liver (VII segment). Vaccinotherapy was initiated after resection of both the primary tumor and the affected lymph nodes . At that time the patient complained of periodic rises in body temperature, marked general weakness, and lymphostasis in the right leg. Eight months later (December 2000) UI revealed several small calcified focuses in both liver lobes; the focal lesions were without signs of their growth. One year later (November 2001) evidence for disease progression was noted: multiple hypoechoic lesions of until 17 mm diameter in the right liver lobe and those of until 13 mm diameter in the abdominal cavity were revealed by UI. Moreover, in the liver multiple hyperechoic inclusions of 2 mm diameter were detected. For this reason vaccinotherapy was intensified. One your later (November 2002) the patient? s status was satisfactory. Multiple calcified focuses of until 8 mm diameter were revealed by UI. In the final analysis, at 4 years after vaccinotherapy no evidence for disease progression was noted.

A 44 year-old female patient D (a history № 007) traumatized her moles on the left upper arm in January 2000. The affected moles became hemorrhaging. Enlargement of the left axillary lymph nodes was noted and melanoma was diagnosed in March 2000. Both the primary tumor (IY stage of invasion; thickness 6 mm) and the affected lymph nodes were surgically ablated. The vaccinotherapy was initiated in April 2000. The treatment was well tolerated without serious side effects. The next day after each vaccination the erythema and induration of 5-to-6 sm diameter was developed in the injection site. In June 2000 disease progression was noted: 3 large (> 10 mm) soft tissue lesions were resected. In July 2000 8 other lesions located in various body regions were also ablated. Regression of multiple small (< 5 mm) subcutaneous lesions was noted in the sites of vaccine injection. With such treatment, a completed remission was achieved that lasted as long as 1 year. In September 2001 a recurrent tumor was surgically ablated in the region of postoperative scar and vaccinotherapy was intensified. No evidence for disease progression was noted over the following 2 years. In September 2003 metastatic lesions were detected in the left mammary gland. For this reason, sectorial resection of the affected tissue was performed, and vaccinotherapy was continued. The complex (surgery + vaccinotherapy) treatment ultimately provided a completed long-term remission. In the final analysis, at 4 years after vaccinotherapy initiation the patient was in good condition, exhibited no signs of disease. There was a complain of lymphostasis in the left arm.

A 42 year -old female patient K (a history № 2069) underwent surgery (resection of a pigmentary focus on a toe) in January 1999. Enlargement of the inguinal lymph node was noted in January 2002. Diagnosis was lymphadenitis. In March 2002 this lymph node was opened and sanified. One month later the lymph node again became inflamed. A histological analysis of the lymph node material revealed melanoma cells. A course of polychemotherapy was conducted in May 2002. A pigmentary focus of 35 mm diameter was detected within the inguinal region on the left in June 2002. This focus was ablated and after which vaccinotherapy was started. At that time there were complains of soreness of the inguinal region on the right, marked general weakness, panhidrosis, and low grade fever The treatment was well tolerated. At 1 year after vaccinotherapy initiation MRI revealed a single rounded lesion focus in IX lung segment. For this reason vaccinotherapy was intensified. Six months later MRI revealed fibrosis in the site of the former lesion focus. In the final analysis, at 3 years after vaccinotherapy initiation the patient was in good condition, and exhibited no signs of disease.

A 19 year-old male patient P (a history № 1001) underwent surgery (resection of a melanoma focus on the right shank) in May 1999. Relapse in the form of developing single metastatic lesion on the left shank was noted in June 2001. Vaccinotherapy was initiated immediately after lesion resection. The treatment was well tolerated. In January 2002 the enlargement of lymph nodes was noted in the inguinal region on the right. A puncture biopsy revealed no tumor cells. In Mart 2003 enlarged lymph nodes were noted within the neck region on the right. In December 2003 the lymph nodes reduced in their sizes to norma. In the final analysis, at 3 years after vaccinotherapy initiation the patient was in good condition, had no complains, exhibited no signs of disease.

For more information see the publications.