Combination of Immunotherapy With Targeted Therapy: Theory and Practice in Metastatic Melanoma

Abstract

Metastatic melanoma is the most aggressive and obstinate skin cancer with poor prognosis. Variant novel applicable regimens have emerged during the past decades intensively, while the most profound approaches are oncogene-targeted therapy and T-lymphocyte mediated immunotherapy. Although targeted therapies generated remarkable and rapid clinical responses in the majority of patients, acquired resistance was developed promptly within months leading to tumor relapse. By contrast, immunotherapies elicited long-term tumor regression. However, the overall response rate was limited. In view of the above, either targeted therapy or immunotherapy cannot elicit durable clinical responses in large range of patients. Interestingly, the advantages and limitations of these regimens happened to be complementary. An increasing number of preclinical studies and clinical trials proved a synergistic antitumor effect with the combination of targeted therapy and immunotherapy, implying a promising prospect for the treatment of metastatic melanoma. In order to achieve a better therapeutic effectiveness and reduce toxicity in patients, great efforts need to be made to illuminate multifaceted interplay between targeted therapy and immunotherapy.

Keywords: combinatorial regimens; immune checkpoint blockade; immunotherapy; metastatic melanoma; targeted therapy.

Figure 1

Timeline of FDA-approved regimens of targeted therapy and immunotherapy for melanoma. Interferon α-2b, IL-2, and peg-IFN were approved for adjuvant therapy. Since 2011, eleven therapies have been approved, including BRAF and MEK inhibitors as single-drug and combinatorial regimens, antibodies against CTLA-4 and PD-1 and the combination of the two.

Figure 2

BRAF^V600E oncogene promotes melanoma cell proliferation and immune evasion. Mutations in BRAF oncogene cause constitutive activation of the MAPK pathway and lead to the uncontrolled proliferation of tumor cells by various mechanisms including induced anti-apoptosis, increased invasiveness, and metastatic behavior. However, activation of MAPK pathway leads to a marked reduction in tumor-associated antigens (TAAs) (MART-1, gp-100, and Trp1/2) through inhibiting transcriptional expression of MITF. Meanwhile, the activation of MAPK pathway could contribute to increased immunosuppressive regulators such as IL-6, IL-10, VEGF, IL-1, and CCL2, as well as enhanced recruitment of TAF and MDSCs. Both downregulation of antigens and upregulation of immunosuppressive factors contribute to immune evasion.

Figure 3

MAPK inhibitors induce melanoma cell death and regulate immune microenvironment. BRAF and MEK inhibitors induce melanoma cell death through suppression of MAPK pathway. The expression of TAAs will be increased by upregulated transcription of MITF when MAPK pathway is blocked. In addition to affecting melanoma cells, MAPK pathway blockade can also abolish the tumor immunosuppressive microenvironment including inhibition of TAFs and downregulation of immunosuppressive factors. Treatment of selective BRAF inhibitors in BRAF wild type lymphocytes leads to paradoxical activation of MAPK pathway by the transactivation of CRAF, thus promoting cell proliferation and function. Although MEK inhibitors may impair T cell function in vitro via MAPK pathway blockade, combination with BRAF inhibitors increased expression of antigens and suppressed immunosuppressive environment. Immune microenvironment also contributes to acquired resistance to BRAF inhibitors.

Figure 4

Targeted therapy and immunotherapy in the cancer-immunity cycle. The generation of antitumoral immune response is complex and involves diverse immune cells and multiple steps which include augmenting TAAs presentation, T cell priming and differentiation, enhancing the infiltration and activity of T cell, and overcoming the immune suppressive signaling. Some of immunotherapies are currently under clinical evaluation. For example, vaccine and T-VEC can promote antigens presentation, anti-CTLA-4 can promote T cell priming, cytokines, anti-PD-1, TIM3, and IDO/TDO inhibitors can promote T cell activation, and ACT therapy can directly transfer reactive and tumor-specific T cells. MAPK inhibitors complement immunotherapy through enhancing TAAs expression, promoting DCs maturation and antigens presentation, T cell infiltration into tumors, impairing immunosuppressive microenvironment, and inducing immunogenic tumor cell death. Adapted from Hughes et al. (47).