Synergistic effects of radiotherapy and targeted immunotherapy in improving tumor treatment efficacy: a review

Radiotherapy (RT), unlike chemotherapy, is one of the most routinely used and effective genotoxic and immune response inducing cancer therapies with an advantage of reduced side effects. However, cancer can relapse after RT owing to multiple factors, including acquired tumor resistance, immune suppressive microenvironment buildup, increased DNA repair, thus favoring tumor metastasis. Efforts to mitigate these undesirable effects have drawn interest in combining RT with immunotherapy, particularly the use of immune checkpoint inhibitors, to tilt the pre-existing tumor stromal microenvironment into long-lasting therapy-induced antitumor immunity at multiple metastatic sites (abscopal effects). This multimodal therapeutic strategy can alleviate the increased T cell priming and decrease tumor growth and metastasis, thus emerging as a significant approach to sustain as long-term antitumor immunity. To understand more about this synergism, a detailed cellular mechanism underlying the dynamic interaction between tumor and immune cells within the irradiated tumor microenvironment needs to be explored. Hence, in the present review, we have attempted to evaluate various RT-inducible immune factors, which can be targeted by immunotherapy and provide detailed explanation to optimally maximize their synergy with immunotherapy for long-lasting antitumor immunity. Moreover, we have critically assessed various combinatorial approaches along with their challenges and described strategies to modify them in addition to providing approaches for optimal synergistic effects of the combination (AU)

Synergistic effects of radiotherapy and targeted immunotherapy in improving tumor treatment efficacy: a review.

Radiotherapy (RT), unlike chemotherapy, is one of the most routinely used and effective genotoxic and immune response inducing cancer therapies with an advantage of reduced side effects. However, cancer can relapse after RT owing to multiple factors, including acquired tumor resistance, immune suppressive microenvironment buildup, increased DNA repair, thus favoring tumor metastasis. Efforts to mitigate these undesirable effects have drawn interest in combining RT with immunotherapy, particularly the use of immune checkpoint inhibitors, to tilt the pre-existing tumor stromal microenvironment into long-lasting therapy-induced antitumor immunity at multiple metastatic sites (abscopal effects). This multimodal therapeutic strategy can alleviate the increased T cell priming and decrease tumor growth and metastasis, thus emerging as a significant approach to sustain as long-term antitumor immunity. To understand more about this synergism, a detailed cellular mechanism underlying the dynamic interaction between tumor and immune cells within the irradiated tumor microenvironment needs to be explored. Hence, in the present review, we have attempted to evaluate various RT-inducible immune factors, which can be targeted by immunotherapy and provide detailed explanation to optimally maximize their synergy with immunotherapy for long-lasting antitumor immunity. Moreover, we have critically assessed various combinatorial approaches along with their challenges and described strategies to modify them in addition to providing approaches for optimal synergistic effects of the combination.

Advances in epidermal growth factor receptor specific immunotherapy: lessons to be learned from armed antibodies.

The epidermal growth factor receptor (EGFR) has been recognized as an important therapeutic target in oncology. It is commonly overexpressed in a variety of solid tumors and is critically involved in cell survival, proliferation, metastasis, and angiogenesis. This multi-dimensional role of EGFR in the progression and aggressiveness of cancer, has evolved from conventional to more targeted therapeutic approaches. With the advent of hybridoma technology and phage display techniques, the first anti-EGFR monoclonal antibodies (mAbs) (Cetuximab and Panitumumab) were developed. Due to major limitations including host immune reactions and poor tumor penetration, these antibodies were modified and used as guiding mechanisms for the specific delivery of readily available chemotherapeutic agents or plants/bacterial toxins, giving rise to antibody-drug conjugates (ADCs) and immunotoxins (ITs), respectively. Continued refinement of ITs led to deimmunization strategies based on depletion of B and T-cell epitopes or substitution of non-human toxins leading to a growing repertoire of human enzymes capable of inducing cell death. Similarly, the modification of classical ADCs has resulted in the first, fully recombinant versions. In this review, we discuss significant advancements in EGFR-targeting immunoconjugates, including ITs and recombinant photoactivable ADCs, which serve as a blueprint for further developments in the evolving domain of cancer immunotherapy.

Desensitization of metastatic melanoma cells to therapeutic treatment through repeated exposure to dacarbazine.

Aberrant anti-cancer drug efflux mediated by membrane protein ABC transporters (ABCB5 and ABCG2) is thought to characterize melanoma heterogeneous chemoresistant populations, presumed to have unlimited proliferative and self-renewal abilities. Therefore, this study primarily aimed to investigate whether continuous exposure of melanoma cells to dacarbazine (DTIC) chemotherapeutic drug enriches cultures with therapy resistant cells. Thereafter, we sought to determine whether combining the genotoxic activity of DTIC with the oxidative insults of hypericin activated photodynamic therapy (HYP-PDT) could synergized to kill heterogenous chemoresistant melanoma populations. This study revealed that DTIC resistant (UCT Mel-1DTICR2) melanoma cells were less sensitive to all therapies than parental melanoma cells (UCT Mel-1), yet combination therapy was the most efficient. At the exception of DTIC treatment, both HYP-PDT and the combination therapy were effective in significantly reducing the Hoechst non-effluxing dye melanoma main populations (MP) compared to their side population (SP) counterparts. Likewise, HYP-PDT and combination therapy significantly reduced self-renewal capacity, increased expression of ABCB5 and ABCG2 transporters and differentially induced cell cycle arrest and cell death (apoptosis or necrosis) depending on the melanoma MP cell type. Collectively, combination therapy could synergistically reduce melanoma proliferative and clonogenic potential. However, further research is needed to decipher the cellular mechanisms underlying this resistance which would enable combination therapy to reach therapeutic fruition.

Antibody-Based Immunotherapy: Alternative Approaches for the Treatment of Metastatic Melanoma.

Melanoma is the least common form of skin cancer and is associated with the highest mortality. Where melanoma is mostly unresponsive to conventional therapies (e.g., chemotherapy), BRAF inhibitor treatment has shown improved therapeutic outcomes. Photodynamic therapy (PDT) relies on a light-activated compound to produce death-inducing amounts of reactive oxygen species (ROS). Their capacity to selectively accumulate in tumor cells has been confirmed in melanoma treatment with some encouraging results. However, this treatment approach has not reached clinical fruition for melanoma due to major limitations associated with the development of resistance and subsequent side effects. These adverse effects might be bypassed by immunotherapy in the form of antibody-drug conjugates (ADCs) relying on the ability of monoclonal antibodies (mAbs) to target specific tumor-associated antigens (TAAs) and to be used as carriers to specifically deliver cytotoxic warheads into corresponding tumor cells. Of late, the continued refinement of ADC therapeutic efficacy has given rise to photoimmunotherapy (PIT) (a light-sensitive compound conjugated to mAbs), which by virtue of requiring light activation only exerts its toxic effect on light-irradiated cells. As such, this review aims to highlight the potential clinical benefits of various armed antibody-based immunotherapies, including PDT, as alternative approaches for the treatment of metastatic melanoma.