Neoadjuvant Immunotherapy in High-Risk Melanoma: A New Approach




Neoadjuvant immunotherapy can induce very effective autoimmunization specific to each patient’s melanoma and result in tumor ablation. It is nontoxic, safe, well tolerated, and relatively less expensive than any other adjuvant approach.
— E. George Elias, MD, PhD

Melanoma is an immunogenic tumor, as it expresses various melanoma-specific antigens. However, it is both biologically and clinically heterogeneous. Biologically, it expresses different melanoma antigens and has diverse genetic profiles among different patients. Clinically, it varies in the amount of pigmentation and sometimes appears in sun-exposed areas but may also occur in non–sun-exposed skin. The initial pattern spread varies, as some melanomas metastasize to the regional lymph nodes, whereas others metastasize to different viscera.

To overcome such heterogeneity and obtain an effective antitumor immune response, a tumor-specific and autogenic therapeutic approach could be essential. The patient’s own tumor, prior to its excision, can be utilized in vivo as the source for melanoma-specific antigens and to activate the local immune cells within the tumor site. Such an idea is supported by two reports.

First, it has been shown that patients with resected metastases who have melanoma-specific tumor-infiltrating lymphocytes in their metastases have statistically better survival than those who have melanoma-specific T cells in their peripheral blood.1 The second report showed that the higher the number of tumor-infiltrating lymphocytes at the primary site of melanoma, the better the patient’s prognosis.2 Therefore, it was logical to activate these immune cells at the tumor site, which could induce an autologous antitumor immune response locally and then systemically.

That being said, two cytokines have been shown to activate these tumor-infiltrating lymphocytes when administered intralesionally: granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine)3-6 and interleukin-2 (IL-2, Proleukin).7-9 Neither of these two cytokines has any direct cytotoxic activity on tumor cells, but their biologic effect is mediated in vivo via mononuclear cells.

Experimental Model

Patients with dermal and subdermal metastases were initially studied to evaluate the effect of each of these two cytokines. They were chosen because their lesions were accessible for intralesional therapy and could be inspected, palpated, and easily biopsied, regardless of the extent of the disease, anatomic site, or previous therapy.

All study patients had experienced failure of a previous therapy—including isolated limb perfusion, limb infusion, intralesional bacillus Calmette-Guérin, or previous systemic adjuvant treatment with high doses of the same two cytokines—and developed in-transit metastases. All lesions had undergone pathologic confirmation of melanoma, but none were evaluated for their antigenic or genetic expression.

The objectives of the study were to evaluate the local effects on the tumor at the injection site(s) and to determine if there were any systemic side effects or benefits in treated patients, such as prolongation of disease-free survival and overall survival. Each patient received intralesional GM-CSF at 500 µg once per week. If GM-CSF failed to establish a complete response locally over 2 weeks, intralesional IL-2 was substituted at 11 million IU once weekly.

Major Findings

Fifty percent of lesions ≤ 1 cm showed a complete response to GM-CSF therapy, and those in whom GM-CSF failed had a complete response to intralesional IL-2. On the other hand, larger sclerotic lesions failed to respond to either cytokine therapy.

Patients with distant metastases had complete responses at the injected lesions with either cytokine, without any response at the distant metastases. The only exception was a patient with metastases in the lymph nodes of the neck and to the left iliac lymph node who received GM-CSF in several nodes in the neck and had a complete response in all affected nodes. Patients who had failure of systemic adjuvant therapy and developed in-transit metastases had complete responses to intralesional therapy.10,11

There were no clinical complaints and no side effects except for a mild to moderate skin reaction at the injection sites. There were no significant changes in complete blood cell counts, serum chemistries, and, specifically, lactate dehydrogenase. There was no evidence of disease dissemination from either cytokine therapy.

Some sites of complete response were rebiopsied 6 to 8 weeks after the cessation of therapy, which revealed no residual tumor or mononuclear cell infiltrates. This could indicate an immense antitumor immune response at the injected lesions with complete washout of the local therapeutic effect over 6 to 8 weeks.

Thus, some melanoma lesions responded to GM-CSF, whereas others required IL-2. It therefore seemed logical to utilize sequential intralesional administration of both cytokines on 2 consecutive days, 1 week before the standard surgical resection. GM-CSF was administered first to activate the antigen-presenting cells capable of processing the melanoma antigens at the tumor site and then pass the information by crosstalk to T lymphocytes, which were activated on the second-day injection of IL-2. This constituted the new neoadjuvant immunotherapy.

Patients who were not previously treated included those with primary invasive cutaneous melanoma with > 1 mm depth of invasion, satellitosis, in-transit metastases, and/or regional lymph node metastases, who are at high risk of recurrence and metastasis (ie, stage III disease). These patients were surgical candidates but with a guarded prognosis. They were managed by the neoadjuvant immunotherapy.

The Technique

After obtaining a punch biopsy to establish the diagnosis and prior to the surgical resection of the melanoma, each patient received GM-CSF, 500 µg, at the primary site and the dermal metastases on day 1. This was followed by IL-2, 11 million IU, at the same sites on day 2. A week to 10 days later, the patient underwent the planned surgical resection.

The clinical response could not be assessed because of the local reaction at the injected tumor sites. However, the histopathologic examination of the resected tissues revealed complete tumor necrosis with massive histiocytosis at the injected sites.

The immune-histochemical studies on resected tissues showed overexpression of several immune cells at the injected sites and in some regional lymph nodes, including CD3-positive T cells, CD8-positive cytotoxic T cells, CD4-positive helper T cells, and CD83-positive mature dendritic cells. This could indicate that the immune response at the injection sites was transmitted initially to the regional lymph nodes.

All responders, who were at very high risk, had an overall survival that ranged from 3 to 7 years, to the last date of contact, with a median of 4 years.

Benefits and Caveats

Neoadjuvant immunotherapy can induce very effective autoimmunization specific to each patient’s melanoma and result in tumor ablation. It is nontoxic, safe, well tolerated, and relatively less expensive than any other adjuvant approach.

It is effective in small lesions, regardless of their number or location. It seems to be effective in high-risk primary lesions as well as in metastatic lesions. It seems to target the whole tumor cell regardless of an antigenic or genetic profile.

It may be dependent on the tumor microenvironment, but this remains to be determined. It may play a role in intralymphatic administration, as seen in the one patient who had a complete response in distant lymph node metastases after receiving the cytokines in some palpable metastatic neck nodes.

It has been shown that the route of administration of a vaccine can be a critical variable in determining the outcome of an immune response. In an animal model, when a vaccine with naked antigen–encoding RNA was administered in the skin, subcutaneous tissue, or near a lymph node, no significant immune response has been noted. However, when this vaccine was administered in a lymph node, it elicited potent prophylactic and therapeutic antitumor immunity.12

Neoadjuvant therapy with these two cytokines may be applicable to other small-sized malignancies that can be palpated or reached by radiologic means such as ultrasound or computed tomography scan. In addition, patients with distant metastases and lesions might be given intralesional therapy to initiate an antitumor response, but if such therapy cannot be maintained because the lesions dissolve, systemic support with GM-CSF and IL-2 may be needed.

Nevertheless, this approach has its limitations: It is not effective in large sclerotic lesions. In addition, it should not be used in infected lesions or with any allogeneic material such as allogeneic whole-cell melanoma or its lysate, peptides, or nonspecific antigens, as they may cause immune deviation.

Indeed, two reports have appeared in the literature showing that the administration of GM-CSF with peptides or allogeneic whole-cell melanoma was not beneficial and, in fact, proved harmful.13,14 But the antigens used were nonspecific and caused immune deviation by recognizing the peptides or the allogeneic cell vaccine, which had no bearing on the patient’s own tumor.

To take this strategy further, a phase I clinical trial is needed. ■

Adapted from a presentation at the International Conference on Cancer Research and Targeted Therapy, October 22, 2016, in Baltimore.

Disclosure: Dr. Elias reported no potential conflicts of interest.

References

1. Haanen JB, Baars A, Gomez R, et al: Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol Immunoth 55:451-458, 2006.

2. Azimi F, Scolyer RA, Rumcheva P, et al: Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 30:2678-2683, 2012.

3. Si Z, Hersey P, Coats AS: Clinical responses and lymphoid infiltrates in metastatic melanoma following treatment with intralesional GM-CSF. Melanoma Res 6:247-255, 1996.

4. Nasi ML, Lieberman P, Busam KJ, et al: Intradermal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with metastatic melanoma recruits dendritic cells. Cytokines Cell Mol Ther 5:139-144, 1999.

5. Vaquerano JE, Cadbury P, Tressler P, et al: Regression of in-transit melanoma or the scalp with intralesional recombinant human granulocyte-macrophage colony-stimulating factor. Arch Dermatol 135:1276-1277, 1999.

6. Hoeller C, Jansen B, Heere-Ress E, et al: Perilesional injection of r-GM-CSF in patients with cutaneous melanoma metastases. J Invest Dermatol 117:371-374, 2011.

7. Radny P, Caroli UM, Bauer J, et al: Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases. Br J Cancer 89:1620-1626, 2003.

8. Dehesa LA, Vilar-Alejo J, Valeron-Almazan P, et al: Experience in the treatment of cutaneous in-transit melanoma metastases and satellitosis with intralesional interleukin-2. Actas Derrnosifiliogr 100:571-585, 2009.

9. Weid B, Derhovanessian E, Pflugfelder A, et al: High response rate after intratumoral treatment with interleukin-2: Results from a phase 2 study in 51 patients with metastasized melanoma. Cancer 116:4139-4146, 2010.

10. Elias EG, Sharma BK: Melanoma vaccines, revisited: A review. G Ital Dermatol Venereol 149:711-717, 2014.

11. Elias EG: Intralesional cytokine therapy in cutaneous melanoma: A call for clinical trials. Letter to the editor. The ASCO Post 4(17):103, 2013.

12. Kreiter S, Selmi A, Diken M, et al: Intranodal vaccination with naked antigen-encoding RNA elicited potent prophylactic and therapeutic antitumor immunity. Cancer Res 70:9031-9040, 2010.

13. Singluff CL, Petroni GR, Olson WC, et al: Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell response to multipeptide melanoma vaccine: Outcome of a multicentric randomized trial. Clin Cancer Res 15:7036-7044, 2009.

14. Faries MB, Hsueh EC, Xe Y, et al: Effect of granulocyte/macrophage colony-stimulating factor on vaccination with an allogeneic whole-cell melanoma vaccine. Clin Cancer Res 15:7029-7035, 2009.



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