Immunotherapy in Cancer: A Combat between Tumors and the Immune System; You Win Some, You Lose Some

Abstract

Cancer immunotherapy has emerged as a treatment modality, mainly as the result of discoveries in the immune response regulation, including mechanisms that turn off immune responses. Immunogenic cutaneous melanoma is a canonical model for therapeutic immunotherapy studies. “Passive” immunotherapy with monoclonal antibodies (mAbs) has outpaced “active” immunotherapy with anti-tumor vaccines, and mAbs that antagonize the off responses have been recently introduced in clinical practice. Despite these recent successes, many unresolved practical and theoretical questions remain. Notably unknown are the identity of the lymphocytes that eliminate tumor cells, which white cells enter into tumors, through which endothelium, in what order, and how they perform their task. The parameters of size and location that could be used to determine in which tumors the immune response may be sufficient to eradicate the tumor are yet unknown. Immunotherapy has been so far more efficient to treat solid and hematologic tumors located outside the central nervous system, than primary brain tumors and brain metastases. In contrast to recent advances with mAbs, anti-tumor vaccine development has been lagging behind. The multiplicity of antigens that must be targeted to achieve significant clinical response is partially responsible for this lag, especially in melanoma, one of the most mutated tumors. Further hampering vaccination results is the fact that tumor elimination by the immune system is the result of a race between tumors with different growth rates and the relatively slow development of the adaptive immune response. The enhancement of the native arm of the immune response or the administration of targeted chemotherapy to slow tumor development, are approaches that should be studied. Finally, criteria used to analyze patient response to immunotherapeutic treatments must be perfected, and the patient populations that could benefit the most from this approach must be better defined.

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

“…Several kinds, compositions, and modes of administration of anti-tumor vaccines have been used with different results [160,161,162,163,164,165,166,167]. More recently, the focus of anti-tumor vaccines has been moved from tumor cells to TME too [7,9,10,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175]. Indeed, the possibility of targeting tumor endothelial cells or the VEGF signaling axis with specific vaccines has been assessed in preclinical studies, and clinical trials are ongoing [168].…”

Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes

“…It is possible that irAEs may be associated with durable response and clinical benefit, and that association has previously been studied with anti-CTLA-4 therapy (19), although contradictory reports exist (20). Investigation is currently underway to develop predictive indicators of successful anti-PD1 therapy, including tumor PD-L1 expression and tumor immune infiltrate (21–23) and other potential biomarkers (24), however there has been no published investigation of whether the irAE profile of anti-PD1 therapy is associated with disease outcomes.…”

Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies

“…Upregulation of checkpoint molecules has been suggested as one of the main mechanisms of adaptive resistance in adoptive T-cell therapies [171], and evidence has continued to accumulate to support a key role of the PD-1/PD-L1 axis in attenuating anti-tumor immune responses [172,173]. Although PD-1/PD-L1 expression may not be robust at the time of diagnosis, they can be rapidly induced following blinatumomab treatment and is associated with disease relapse and resistance [174,175].…”