RE:RE:RE:RE:Accelerated Approval ahead of AUA congress would spark I don't think pdt is used for melanoma yet although it is used for other forms of skin cancer.
Dr. McFarland got a research grant for this and published a 2022 paper where she demonstrates how new next-generation NIR Ru PSs ML19B01 and ML19B02 create a strong anti-melanoma cell immune response. Hopefully, one day soon, Theralase will be able to take advantage of this research with a clinical trial.
Immunomodulating Ruthenium Metal Complexes for Melanoma PhotodynamicTherapy Photodynamic therapy of melanoma with new, structurally similar, NIR-absorbing ruthenium (II) complexes promotes tumor growth control via distinct hallmarks of immunogenic cell death Published online 2022 Jan 15.
Prathyusha Konda, John A Roque I, Liubov M Lifshits, Angelita Alcos, Eissa Azzam, Ge Shi, Colin G Cameron, Sherri A McFarland, Shashi Gujar
Abstract
Cancer therapies that generate T cell-based anti-cancer immune responses are critical for clinical success and are favored over traditional therapies. One way to elicit T cell immune responses and generate long-lasting anti-cancer immunity is through induction of immunogenic cell death (ICD), a form of regulated cell death that promotes antigenicity and adjuvanticity within dying cells. Therefore, research in the last decade has focused on developing cancer therapies which stimulate ICD. Herein, we report novel photodynamic therapy (PDT) compounds with immunomodulatory and ICD inducing properties. PDT is a clinically approved, minimally invasive anti-cancer treatment option and has been extensively investigated for its tumor-destroying properties, lower side effects, and immune activation capabilities. In this study, we explore two structurally related ruthenium compounds, ML19B01 and ML19B02, that can be activated with near infrared light to elicit superior cytotoxic properties. In addition to its direct cell killing abilities, we investigated the effect of our PSs on immunological pathways upon activation. PDT treatment with ML19B01 and ML19B02 induced differential expression of reactive oxygen species, proinflammatory response-mediating genes, and heat shock proteins. Dying melanoma cells induced by ML19B01-PDT and ML19B02-PDT contained ICD hallmarks such as calreticulin, ATP, and HMGB1, initiated activation of antigen presenting cells, and were efficiently phagocytosed by bone marrow-derived dendritic cells. Most importantly, despite the distinct profiles of ICD hallmark inducing capacities, vaccination with both PDT-induced dying cancer cells established anti-tumor immunity that protected mice against subsequent challenge with melanoma cells.
Introduction
Cancer immunotherapies hold tremendous promise in clinics due to their ability to harness the patient’s own immune system to attack tumor cells [1]. Several immunotherapies have been developed by targeting different phases of the cancer-immunity cycle, such as immune checkpoint inhibitors, adoptive T cell transfer therapies, and cancer vaccines [2-5]. T cell-based immunotherapies have become a central focus for generating durable anti-cancer immune responses, due to their capacity for recognizing and eradicating malignant cells through cancer-specific antigen-directed cytotoxicity [5]. Furthermore, T cell infiltration in the tumor microenvironment (TME) has been correlated with control of tumor progression and is deemed a critical factor in the efficacy of immunotherapies [5-8]. Professional antigen presenting cells (APCs) such as dendritic cells (DCs) play a crucial role in the initiation of these T cell-based immune responses by presenting tumor antigens to T cells thereby activating them [9]. Consequently, therapeutic interventions that promote the DC-T cell-based anti-cancer immunity are highly desired.
In this context, immunogenic cell death (ICD) has garnered attention in recent times, as this form of regulated cell death can activate DCs, induce anti-tumor T cell responses, and generate beneficial long-lasting immunity [10-12]. ICD encompasses diverse ‘hallmarks’ that ultimately involve two major aspects of anti-tumor T cell response: antigenicity and adjuvanticity. Dying cells undergoing ICD provide access to cancer antigens, which contributes to the antigenicity aspect of ICD [13,14]. In addition, danger-associated molecular patterns (DAMPs) are emitted spatiotemporally and function as adjuvants in ICD mediated anti-tumor immunity. These DAMPs promote the recruitment and activation of APCs such as DCs by binding to specific pattern recognition receptors (PRRs) on their surface [9,15,16]. Activated DCs engulf dying cancer cells, process cancer antigens, and participate in cross-presentation of antigenic peptides to CD8+ T cells, hence activating them and initiating the anti-tumor immune response [9,17-20]. Numerous preclinical and clinical studies suggest the prognostic and predictive value for DAMPs and associated processes in cancer treatment prognosis [21]. Together, ICD facilitates overturning the TME by recruiting immune cells to the tumor site and converting “cold” tumors to “hot”. Therefore, the development of next generation anti-cancer modalities with ICD-inducing properties can improve the clinical outcomes for cancers. Recent efforts have focused on evaluating previously approved chemotherapeutics and developing new agents and therapies for ICD-inducing capabilities [22].
Photodynamic therapy (PDT) is a clinically approved anti-cancer modality that can be used alone or as an adjuvant delivered alongside surgery or other therapies [23]. PDT employs a light-responsive prodrug, known as a photosensitizer (PS), to sensitize cytotoxic reactive oxygen species (ROS) that directly destroy tumors and tumor vasculature [24-28]. The PDT reaction is confined to regions where the PS, light, and oxygen overlap in space and time, thus providing tumor selectivity and fewer side effects compared to conventional therapies. Besides its cytotoxic properties, studies have shown that PDT-induced oxidative stress effectively initiates an inflammatory response and causes the infiltration of immune cells at the treatment site [26,29,30]. The acute inflammatory response from PDT is also implicated in the development of adaptive anti-tumor immune responses [31-33]. Recently, PDT has been investigated for its ability to produce ICD and anti-tumor immune responses [34-36], and approaches to improve ICD-inducing capabilities of PDT are being developed [37,38]. Here, we report the discovery of new ICD-inducing, near infrared (NIR) absorbing ruthenium-based PSs as PDT agents for targeting aggressive melanoma [39,40].
ML19B01 and ML19B02 are tris heteroleptic Ru(II) complexes containing a chromophoric ligand to shift the absorption into the NIR and a PDT ligand for sensitizing singlet oxygen. Activation of the PS in the NIR window is advantageous for deeper tissue penetration and thus treating a wider tumor margin and may be especially important for highly pigmented melanomas where melanin can effectively compete for light absorption of the shorter wavelengths. PDT generally employs red light and designing new PSs that can be activated with longer wavelength NIR light while maintaining potent photocytotoxic effects has been a major challenge to the field of PS design for PDT. Herein, we not only overcome this hurdle but also demonstrate that both PSs have similar cytotoxic potential but differ in their ICD hallmark-promoting capacities. Additionally, both PDT treatments emit DAMPs in vitro and are efficiently phagocytosed by bone marrow-derived dendritic cells (BMDCs). Using dying cancer cells as tumor vaccination modalities, we demonstrate that the PSs lead to a delay in tumor growth and improve tumor-free survival in the highly aggressive B16F10 mouse melanoma model.