Immunotherapy Modalities Research Articles

Abstract 6244: A T cell engaging bispecific antibody utilizing a bivalent tumor-selective folate receptor alpha binding arm for the treatment of ovarian cancer

Abstract The use of T cell engagers (TCEs) to treat solid tumors in humans is challenging, and several have been limited by narrow therapeutic windows due to substantial toxicity. Dose-limiting toxicities of TCEs include cytokine release syndrome (CRS) and on-target, off-tumor toxicities since many solid tumor target antigens are also expressed in healthy tissues, albeit at lower levels. While there have been improvements in the clinical management of immune-mediated toxicities such as CRS, on-target, off-tumor effects remain one of the primary challenges of using TCEs for treatment of solid tumors. Here, we describe TNB-928B, a novel fully human TCE that is bivalent for folate receptor alpha (FRα) that selectively targets FRα overexpressing tumor cells yet avoids targeting cells that express low levels of FRα found in normal human cells. Selectivity is conferred by an avidity effect of the FRα targeting arm in combination with a unique low-affinity CD3 arm and is anticipated to reduce the risk of adverse events in normal cells expressing low levels of FRα. TNB-928B induces preferential effector T cell activation, proliferation, and cytotoxic activity with minimal cytokine release, compared to a positive control containing OKT3, thereby improving the therapeutic index. Moreover, TNB-928B exhibits substantial ex vivo tumor cell lysis using endogenous T cells and is effective in vivo promoting T cell infiltration and tumor regression in mouse models of ovarian cancer. Together, these results demonstrate TNB-928B represents a novel next generation immunotherapy modality with enhanced safety and specificity for the treatment of ovarian cancer. Citation Format: Brian C. Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A. Boudreau, Ben Buelow, Karen Chang, Laura M. Davison, Suhasini Iyer, Vidyut Kalwit, Harbani Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S. Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S. Ugamraj, Roland Buelow, Jocelyn Chapman, Nathan D. Trinklein, Katherine E. Harris. A T cell engaging bispecific antibody utilizing a bivalent tumor-selective folate receptor alpha binding arm for the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6244.

The Role of Toll-like Receptor Agonists and Their Nanomedicines for Tumor Immunotherapy.

Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a critical role in innate and adaptive immunity. Toll-like receptor agonists (TLRa) as vaccine adjuvant candidates have become one of the recent research hotspots in the cancer immunomodulatory field. Nevertheless, numerous current systemic deliveries of TLRa are inappropriate for clinical adoption due to their low efficiency and systemic adverse reactions. TLRa-loaded nanoparticles are capable of ameliorating the risk of immune-related toxicity and of strengthening tumor suppression and eradication. Herein, we first briefly depict the patterns of TLRa, followed by the mechanism of agonists at those targets. Second, we summarize the emerging applications of TLRa-loaded nanomedicines as state-of-the-art strategies to advance cancer immunotherapy. Additionally, we outline perspectives related to the development of nanomedicine-based TLRa combined with other therapeutic modalities for malignancies immunotherapy.

Tracing New Landscapes in the Arena of Nanoparticle-Based Cancer Immunotherapy

Over the past two decades, unique and comprehensive cancer treatment has ushered new hope in the holistic management of the disease. Cancer immunotherapy, which harnesses the immune system of the patient to attack the cancer cells in a targeted manner, scores over others by being less debilitating compared to the existing treatment strategies. Significant advancements in the knowledge of immune surveillance in the last few decades have led to the development of several types of immune therapy like monoclonal antibodies, cancer vaccines, immune checkpoint inhibitors, T-cell transfer therapy or adoptive cell therapy (ACT) and immune system modulators. Intensive research has established cancer immunotherapy to be a safe and effective method for improving survival and the quality of a patient’s life. However, numerous issues with respect to site-specific delivery, resistance to immunotherapy, and escape of cancer cells from immune responses, need to be addressed for expanding and utilizing this therapy as a regular mode in the clinical treatment. Development in the field of nanotechnology has augmented the therapeutic efficiency of treatment modalities of immunotherapy. Nanocarriers could be used as vehicles because of their advantages such as increased surface areas, targeted delivery, controlled surface and release chemistry, enhanced permeation and retention effect, etc. They could enhance the function of immune cells by incorporating immunomodulatory agents that influence the tumor microenvironment, thus enabling antitumor immunity. Robust validation of the combined effect of nanotechnology and immunotherapy techniques in the clinics has paved the way for a better treatment option for cancer than the already existing procedures such as chemotherapy and radiotherapy. In this review, we discuss the current applications of nanoparticles in the development of ‘smart’ cancer immunotherapeutic agents like ACT, cancer vaccines, monoclonal antibodies, their site-specific delivery, and modulation of other endogenous immune cells. We also highlight the immense possibilities of using nanotechnology to accomplish leveraging the coordinated and adaptive immune system of a patient to tackle the complexity of treating unique disease conditions and provide future prospects in the field of cancer immunotherapy.

Combination treatment of radiofrequency ablation and peptide neoantigen vaccination: Promising modality for future cancer immunotherapy.

3151 Background: We previously reported the safety and immunogenicity of a personalized neoantigen-based peptide vaccine, iNeo-Vac-P01, in patients with a variety of cancer types. The current study investigated the synergistic effects between radiofrequency ablation (RFA) and neoantigen vaccination in cancer patients and tumor-bearing mice. Methods: 28 cancer patients were enrolled in this study, including 10 patients who had received RFA treatment within 6 months before scheduled for vaccination, and 18 patients who had not. Individualized neoantigen peptide vaccines were designed, manufactured, and delivered for all patients, followed by subcutaneous administration of GM-CSF as an adjuvant. Mouse models were used to validate the synergistic efficacy of combination treatment of RFA and neoantigen vaccination. Results: Longer median progression free survival (mPFS) and median overall survival (mOS) were observed in patients receiving RFA prior to vaccines compared to patients only receiving vaccines (4.42 and 20.18 months vs. 2.82 and 10.94 months). Ex vivo ELISpot assay showed that patients who received both had stronger IFN-γ responses against patient-specific neoantigens at baseline and post vaccination. Mice receiving RFA together with vaccine displayed higher antitumor immune responses than mice receiving single modality; addition of anti-PD-1 further enhanced the antitumor response. Conclusions: Neoantigen vaccination after RFA treatment led to an overall increase in clinical response and immune response among patients of different cancer types. Combination treatment of both modalities in mice further validated their synergistic antitumor potentials, which could be further enhanced by the addition of anti-PD-1. The mechanisms of their synergies require further investigation. Clinical trial information: NCT03662815.

Phytochemical Engineered Bacterial Outer Membrane Vesicles for Photodynamic Effects Promoted Immunotherapy.

Cancer vaccines are emerging as an attractive modality for tumor immunotherapy. However, their practical application is seriously impeded by the complex fabrication and unsatisfactory outcomes. Herein, we construct bacterial outer membrane vesicles (OMVs)-based in situ cancer vaccine with phytochemical features for photodynamic effects-promoted immunotherapy. By simply fusing thylakoid membranes with OMVs, bacteria-plant hybrid vesicles (BPNs) are prepared. After systemic administration, BPNs can target tumor tissues and stimulate the activation of immune cells, including dendritic cells (DCs). The photodynamic effects derived from thylakoid lead to the disruption of local tumors and then the release of tumor-associated antigens that are effectively presented by DCs, inducing remarkable tumor-specific CD8+T cell responses. Moreover, BPNs can efficiently ameliorate the immunosuppressive tumor microenvironment and further boost immune responses. Therefore, both tumor development and metastasis can be efficiently prevented. This work provides a novel idea for developing a versatile membrane-based hybrid system for highly efficient tumor treatment.

Tumor-Associated Macrophages and Ovarian Cancer: Implications for Therapy.

Simple SummaryOvarian cancer is a highly lethal female malignancy with high rates of advanced stage and recurrent disease. Ovarian cancer is characterized as poorly responsive to immunotherapy. This is hypothesized to be secondary to its highly immunosuppressive and phenotypically “cold” tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are an integral component of the ovarian cancer TME, and predominantly display an M2 protumor phenotype. Ovarian cancer cells and TAMs interact via a complex network of signaling cytokines. Ovarian cancer TAMs are linked to tumor metastasis, angiogenesis, chemoresistance, and poor prognosis. Due to their profound role, TAMs represent a therapeutic target for ovarian cancer immunotherapy. Strategies for targeting TAMs include increasing phagocytosis, decreasing recruitment, decreasing macrophage survival, and repolarizing TAMs to an antitumor phenotype.The tumor microenvironment (TME) has been implicated to play an important role in the progression of ovarian cancer. One of the most important components of the TME is tumor associated macrophages (TAMs). Phenotypically, macrophages are broadly categorized as M1 pro-inflammatory or M2 anti-inflammatory, based on the cytokines and chemokines that they secrete. The tumor microenvironment is associated with macrophages of an M2 phenotype which suppress the surrounding immune environment, assist tumor cells in evading immune targeting, and support tumor growth and metastasis. Contrarily, M1 macrophages help mount an immune response against tumors, and are associated with a more favorable prognosis in solid tumors. One of the characteristic indicators of a poor prognosis in ovarian cancer is the overrepresentation of M2-type TAMs. As such, therapeutic modalities targeting TME and TAMs are of increasing interest. Pharmacological approaches to eliminate TAMs, include decreasing macrophage survival and recruitment and increasing phagocytosis, have been underwhelming. Clinical strategies targeting these macrophage subtypes via repolarization to an M1 antitumoral state deserve increasing attention, and may serve as a new modality for immunotherapy.

Immune Landscape and an RBM38-Associated Immune Prognostic Model with Laboratory Verification in Malignant Melanoma.

Simple SummaryThe primary treatment of malignant melanoma is a classical regimen of surgery combined with chemotherapy, targeted drugs, and immunotherapy. The purpose of this study was to explore the immune response mechanism of RNA binding protein RBM38 in the development of melanoma with the screening of effective immunodiagnostic models and targeted therapy. We found that RBM38, as an oncogene, promotes the proliferation, invasion, and migration of melanoma cells and is associated with immune infiltration and pathways. Our investigation presented the prognostic significance of RBM38-associated immune signature. In addition, this model may provide a potential strategy for improving the survival and immunotherapy of melanoma patients.Background: Current studies have revealed that RNA-binding protein RBM38 is closely related to tumor development, while its role in malignant melanoma remains unclear. Therefore, this research aimed to investigate the function of RBM38 in melanoma and the prognosis of the disease. Methods: Functional experiments (CCK-8 assay, cell colony formation, transwell cell migration/invasion experiment, wound healing assay, nude mouse tumor formation, and immunohistochemical analysis) were applied to evaluate the role of RBM38 in malignant melanoma. Immune-associated differentially expressed genes (DEGs) on RBM38 related immune pathways were comprehensively analyzed based on RNA sequencing results. Results: We found that high expression of RBM38 promoted melanoma cell proliferation, invasion, and migration, and RBM38 was associated with immune infiltration. Then, a five-gene (A2M, NAMPT, LIF, EBI3, and ERAP1) model of RBM38-associated immune DEGs was constructed and validated. Our signature showed superior prognosis capacity compared with other melanoma prognostic signatures. Moreover, the risk score of our signature was connected with the infiltration of immune cells, immune-regulatory proteins, and immunophenoscore in melanoma. Conclusions: We constructed an immune prognosis model using RBM38-related immune DEGs that may help evaluate melanoma patient prognosis and immunotherapy modalities.

The Epstein-Barr Virus Hacks Immune Checkpoints: Evidence and Consequences for Lymphoproliferative Disorders and Cancers.

The Epstein-Barr Virus (EBV) is a gammaherpesvirus involved in the etiopathogenesis of a variety of human cancers, mostly of lymphoid and epithelial origin. The EBV infection participates in both cell transformation and tumor progression, also playing an important role in subverting immune responses against cancers. The homeostasis of the immune system is tightly regulated by inhibitory mechanisms affecting key immune effectors, such as T lymphocytes and NK cells. Collectively known as immune checkpoints, these mechanisms rely on a set of cellular receptors and ligands. These molecules may be candidate targets for immune checkpoints blockade—an emergent and promising modality of immunotherapy already proven to be valuable for a variety of human cancers. The EBV was lately suspected to interfere with the expression of immune checkpoint molecules, notably PD-1 and its ligands, found to be overexpressed in cases of Hodgkin lymphoma, nasopharyngeal, and gastric adenocarcinomas associated with the viral infection. Even though there is compelling evidence showing that the EBV interferes with other immune checkpoint regulators (e.g., CTLA-4, LAG-3, TIM-3, and VISTA), the published data are still scarce. Herein, we discuss the current state of the knowledge on how the EBV interferes with the activity of immune checkpoints regulators, as well as its implications considering the immune checkpoints blockade for clinical management of the EBV-associated malignancies, notably lymphomas.

Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway

BackgroundBispecific T-cell engager (BiTE) molecules induce redirected lysis of cancer cells by T cells and are an emerging modality for solid tumor immunotherapy. While signs of clinical activity have been...

Abstract P3-09-17: Systems-scale characterization of the human immunome in breast cancer for precision medicine

Abstract It becomes more clear that many deleterious cancer mutations could exhibit a 'gain-of-function' (GOF) behavior. Systematic investigation of such mutations has been lacking and largely overlooked. Advances in next-generation sequencing have identified thousands of genomic variants that perturb the normal functions of proteins, further contributing to diverse phenotypic consequences in breast cancer. Alterations in immune-related pathways are common hallmarks of cancer. A comprehensive understanding of how cancer mutations rewire immune signaling networks and functional output in breast cancer is instrumental to realize the full potential of immunotherapy. Here, we systematically interrogated somatic mutations involved in immune signaling that alter immune responses in cancer patients. To do so, we developed a network-based integrative model to prioritize potential immune responder genes. Identified mutations were enriched in essential protein domains and genes identified were associated with responsiveness to multiple immunotherapy modalities. These genes were used to devise an interactome network propagation framework integrated with drug-associated gene signatures to identify potential immunomodulatory drug candidates in breast cancer. Together, our systems-level analysis results help interpret the heterogeneous immune responses among patients and serve as a resource for future functional studies and targeted breast cancer therapeutics. This study is significant and innovative, as it demonstrates that integration of multi-omics data can help identify critical molecular determinants for effective targeted therapeutics. Citation Format: Stephen Yi. Systems-scale characterization of the human immunome in breast cancer for precision medicine [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-17.

Immunotherapeutic treatments for spinal and peripheral nerve tumors: a primer.

Spinal and peripheral nerve tumors are a heterogeneous group of neoplasms that can be associated with significant morbidity and mortality despite the current standard of care. Immunotherapy is an emerging therapeutic option to improve the prognoses of these tumors. Therefore, the authors sought to present an updated and unifying review on the use of immunotherapy in treating tumors of the spinal cord and peripheral nerves, including a discussion on mechanism of action, drug delivery, current treatment techniques, and preclinical and clinical studies. Current data in the literature regarding immunotherapy were collated and summarized. Targeted tumors included primary and secondary spinal tumors, as well as peripheral nerve tumors. Four primary modalities of immunotherapy (CAR T cell, monoclonal antibody, viral, and cytokine) have been reported to target spine and peripheral nerve tumors. Of the primary spinal tumors, spinal cord astrocytomas had the most preclinical evidence supporting immunotherapy success with CAR T-cell therapy targeting the H3K27M mutation, whereas spinal schwannomas and ependymomas had the most evidence reported for monoclonal antibody therapy preclinically. Of the secondary spinal tumors, primary CNS lymphomas demonstrated some clinical response to immunotherapy, whereas multiple myeloma and bone tumor experiences with immunotherapy were largely limited to concept only. Within peripheral nerve tumors, the use of immunotherapy to treat neurofibromas in the setting of syndromes has been suggested in theory, and possible immunotherapeutic targets have been identified in malignant peripheral nerve tumors. To date, there have been 2 clinical trials involving spine tumors and 2 clinical trials involving peripheral nerve tumors that have reported results, all of which are promising but require validation. Immunotherapy to treat spinal and peripheral nerve tumors has become an emerging area of research and interest. A large amount of preclinical data supporting the translation of this therapy into practice, aimed at ameliorating the poor prognoses of specific tumors, have been reported. Future clinical studies for translation will focus on the optimal therapy type and administration route to best target these tumors, which often preclude total surgical resection given their proximity to the neural and vascular elements of the spine.

Current and future perspectives on CAR-T cell therapy for renal cell carcinoma: A comprehensive review.

In the clinical setting of renal cell carcinoma (RCC), immune reactions such as tumor-specific T cell responses can be spontaneous events or can be elicited by checkpoint inhibitors, cytokines, and other immunotherapy modalities. The results from immunotherapy have led to significant advances in treatment methods and patient outcomes. The approval of nivolumab primarily as a second-line monotherapy and the latest approval of novel combination therapies as first-line treatment have established the significance of immunotherapy in the treatment of RCC. In this perspective, chimeric antigen receptor (CAR)-T cell therapy represents a major advance in the developing field of immunotherapy. This treatment modality facilitates T cells to express specific CARs on the cell surface which are reinfused to the patient to treat the analogous tumor cells. After showing treatment potential in hematological malignancies, this new therapeutic approach has become a strong candidate as a therapeutic modality for solid neoplasms. Although CAR-T cell therapy has shown promise and clinical benefit compared to previous T-cell modulated immunotherapies, further studies are warranted to overcome unfavorable physiological settings and hindrances such as the lack of specific molecular targets, depletion of CAR-T cells, a hostile tumor microenvironment, and on/off-tumor toxicities. Several approaches are being considered and research is ongoing to overcome these problems. In this comprehensive review, we provide the rationale and preliminary results of CAR-T cell therapy in RCC and discuss emerging novel strategies and future directions.

Immunotherapy in soft tissue and bone sarcoma: unraveling the barriers to effectiveness.

Sarcomas are uncommon malignancies of mesenchymal origin that can arise throughout the human lifespan, at any part of the body. Surgery remains the optimal treatment modality whilst response to conventional treatments, such as chemotherapy and radiation, is minimal. Immunotherapy has emerged as a novel approach to treat different cancer types but efficacy in soft tissue sarcoma and bone sarcoma is limited to distinct subtypes. Growing evidence shows that cancer-stroma cell interactions and their microenvironment play a key role in the effectiveness of immunotherapy. However, the pathophysiological and immunological properties of the sarcoma tumor microenvironment in relation to immunotherapy advances, has not been broadly reviewed. Here, we provide an up-to-date overview of the different immunotherapy modalities as potential treatments for sarcoma, identify barriers posed by the sarcoma microenvironment to immunotherapy, highlight their relevance for impeding effectiveness, and suggest mechanisms to overcome these barriers.

Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1.

Ovarian cancer (OC) is the most lethal gynecologic malignancy, affecting approximately 1 in 70 women with only 45% surviving 5 years after diagnosis. This disease typically presents at an advanced stage, and optimal debulking with platinum-based chemotherapy remains the cornerstone of management. Although most ovarian cancer patients will respond effectively to current management, 70% of them will eventually develop recurrence and novel therapeutic strategies are needed. There is a rationale for immune-oncological treatments (IO) in the managements of patients with OC. Many OC tumors demonstrate tumor infiltrating lymphocytes (TILs) and the degree of TIL infiltration is strongly and reproducibly correlated with survival. Unfortunately, results to date have been disappointing in relapsed OC. Trials have reported very modest single activity with various antibodies targeting PD-1 or PD-L1 resulting in response rate ranging from 4% to 15%. This may be due to the highly immunosuppressive TME of the disease, a low tumor mutational burden and low PD-L1 expression. There is an urgent need to improve our understanding of the immune microenvironment in OC in order to develop effective therapies. This review will discuss immune subpopulations in OC microenvironment, current immunotherapy modalities targeting these immune subsets and data from clinical trials testing IO treatments in OC and its combination with other therapeutic agents.

Immune Cell-Derived Extracellular Vesicles - New Strategies in Cancer Immunotherapy.

Immune cell-derived extracellular vesicles (EVs) have increasingly become the focus of research due to their unique characteristics and bioinspired applications. They are lipid bilayer membrane nanosized vesicles harboring a range of immune cell-derived surface receptors and effector molecules from parental cells. Immune cell-derived EVs are important mediators of intercellular communication that regulate specific mechanisms of adaptive and innate immune responses. However, the mechanisms underlying the antitumor effects of EVs are still being explored. Importantly, immune cell-derived EVs have some unique features, including accessibility, storage, ability to pass through blood-brain and blood-tumor barriers, and loading of various effector molecules. Immune cell-derived EVs have been directly applied or engineered as potent antitumor vaccines or for the diagnosis of clinical diseases. More research applications involving genetic engineering, membrane engineering, and cargo delivery strategies have improved the treatment efficacy of EVs. Immune cell-derived EV-based therapies are expected to become a separate technique or to complement immunotherapy, radiotherapy, chemotherapy and other therapeutic modalities. This review aims to provide a comprehensive overview of the characteristics and functions of immune cell-derived EVs derived from adaptive (CD4+ T, CD8+ T and B cells) and innate immune cells (macrophages, NK cells, DCs, and neutrophils) and discuss emerging therapeutic opportunities and prospects in cancer treatment.

Next-Generation Implementation of Chimeric Antigen Receptor T-Cell Therapy Using Digital Health.

Chimeric antigen receptor T-cell (CAR-T) therapy is a paradigm-shifting immunotherapy modality in oncology; however, unique toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome limit its ability to be implemented more widely in the outpatient setting or at smaller-volume centers. Three operational challenges with CAR-T therapy include the following: (1) the logistics of toxicity monitoring, ie, with frequent vital sign checks and neurologic assessments; (2) the specialized knowledge required for toxicity management, particularly with regard to CRS and immune effector cell-associated neurotoxicity syndrome; and (3) the need for high-quality symptomatic and supportive care during this intensive period. In this review, we explore potential niches for digital innovations that can improve the implementation of CAR-T therapy in each of these domains. These tools include patient-facing technologies and provider-facing platforms: for example, wearable devices and mobile health apps to screen for fevers and encephalopathy, electronic patient-reported outcome assessments-based workflows to assist with symptom management, machine learning algorithms to predict emerging CRS in real time, clinical decision support systems to assist with toxicity management, and digital coaching to help maintain wellness. Televisits, which have grown in prominence since the novel coronavirus pandemic, will continue to play a key role in the monitoring and management of CAR-T-related toxicities as well. Limitations of these strategies include the need to ensure care equity and stakeholder buy-in, both operationally and financially. Nevertheless, once developed and validated, the next-generation implementation of CAR-T therapy using these digital tools may improve both its safety and accessibility.

Inhibition of topoisomerase I shapes antitumor immunity through the induction of monocyte-derived dendritic cells.

Understanding the rationale of combining immunotherapy and other anticancer treatment modalities is of great interest because of interpatient variability in single-agent immunotherapy. Here, we demonstrated that topoisomerase I inhibitors, a class of chemotherapeutic drugs, can alter the tumor immune landscape, corroborating their antitumor effects combined with immunotherapy. We observed that topotecan-conditioned TC-1 tumors were occupied by a vast number of monocytic cells that highly express CD11c, CD64, and costimulatory molecules responsible for the favorable changes in the tumor microenvironment. Ly6C+MHC-II+CD11chiCD64hi cells, referred to as topotecan-induced monocyte-derived dendritic cells (moDCs), proliferate and activate antigen-specific CD8+ T cells to levels equivalent to those of conventional DCs. Phenotypic changes in Ly6C+ cells towards moDCs were similarly induced by exposure to topotecan in vitro, which was more profoundly facilitated in the presence of tumor cells. Notably, anti-M-CSFR reversed the acquisition of DC-like properties of topotecan-induced moDCs, leading to the abolition of the antitumor effect of topotecan combined with a cancer vaccine. In short, topoisomerase I inhibitors generate monocyte-derived antigen-presenting cells in tumors, which could be mediated by M-CSF-M-CSFR signaling.

ROBUST INFLAMMATORY RESPONSE AFTER BRONCHOSCOPIC PHOTODYNAMIC THERAPY IN A PATIENT ON IMMUNOTHERAPY

TOPIC: Lung Cancer TYPE: Fellow Case Reports INTRODUCTION: It is well established that photodynamic therapy (PDT) results in both direct tumor cell death as well as immune cell stimulation through processing of antigens from destroyed tumor cells by dendritic cells, which in turn serve as antigen presenting cells to T cells. However, tumor cells adapt varying degrees of immune cell evasion. Systemic immunotherapy with blockade of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is increasingly used to treat various cancers. CASE PRESENTATION: Our patient is a 55-year-old male smoker with a history of stage III (T3N1M0) non-small cell lung cancer (squamous) of the right lower lobe who is status post definitive treatment with carboplatin/taxol and radiation therapy followed by maintenance durvalumab. Several months after treatment, he underwent bronchoscopy that showed endobronchial lesions in the left and right upper lobes as well as in the left lower lobe. Pathology showed squamous cell carcinoma in situ features suspicious for superficial invasion. The decision was made to perform endobronchial photodynamic therapy (PDT) using 630 nm laser at a dose of 200 Joules/cm. In the days after PDT, he routinely underwent repeat bronchoscopy for removal of necrotic tissue resulting from the treatment. However, at one month post-PDT treatment, surveillance bronchoscopy showed ongoing inflammatory changes and necrotic tissue which again required debridement with cryotherapy. He appeared to have a particularly robust response to the PDT therapy which was evident on serial bronchoscopies. DISCUSSION: It is unclear whether the robust response to PDT while on darvalumab was beneficial, detrimental, or neutral to our patient. There are interesting recent experiments using mouse cancer models that show that combining PDT induces increased tumor expression of PD-L1, and that combining local PDT with systemic immunotherapy may actually potentiate the effects of immunotherapy even at distant metastases (Bao et al., Xu et al.). In humans, it is possible that a PDT dose adjustment is needed for patients on systemic immunotherapy. Alternatively, since this robust response was likely the result of increased immunologic activity, it is possible that more immunologic memory is generated which could protect against recurrence or distant spread.Our current arsenal to treat cancer has many modalities, including surgery, chemotherapy, immunotherapy, radiation therapy, and endoscopic modalities. As more modalities are developed and refined, it is crucial to investigate how they can be combined synergistically to provide the best outcomes for patients. CONCLUSIONS: It is unclear whether systemic immunotherapy has an impact on PDT in humans. As both modalities rely on patients' immune systems, studying the combination of PDT with immunotherapy is a compelling area for future research. REFERENCE #1: Shafirstein G et al. Photodynamic Therapy of Non-Small Cell Lung Cancer. Narrative Review and Future Directions. Ann Am Thorac Soc. 2016 Feb;13(2):265-75 REFERENCE #2: Bao R et al. Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276-Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature. Mol Pharm. 2019 Jan 7;16(1):339-348. REFERENCE #3: Xu J et al. Near-Infrared-Triggered Photodynamic Therapy with Multitasking Upconversion Nanoparticles in Combination with Checkpoint Blockade for Immunotherapy of Colorectal Cancer. ACS Nano. 2017 May 23;11(5):4463-4474. DISCLOSURES: No relevant relationships by Martin Vonau, source=Web Response Consultant relationship with Pinnacle Biologics Please note: $1001 - $5000 by Benjamin Young, source=Web Response, value=Consulting fee Removed 04/20/2021 by Benjamin Young, source=Web Response Consultant relationship with Auris Surgical Robotics Please note: $1001 - $5000 by Benjamin Young, source=Web Response, value=Consulting fee Removed 04/20/2021 by Benjamin Young, source=Web Response Consultant relationship with Pinnacle Biologics Please note: 2018-2019 Added 04/30/2021 by Benjamin Young, source=Web Response, value=Consulting fee

Efficacy of Subcutaneous and Sublingual Immunotherapy for House Dust Mite Allergy: A Network Meta-Analysis–Based Comparison

Meta-analyses comparing the efficacy of sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) for house dust mite allergy are lacking. To compare the efficacy of SLIT drops, SLIT tablets, and SCIT in patients with perennial allergic rhinitis through network analysis. Frequentist network meta-analyses estimated the standardized mean difference (SMD) across the three immunotherapy modalities on allergic rhinitis symptom and medication score data from double-blind randomized clinical trials. Random effects models were investigated. We included 26 double-blind randomized clinical trials in this meta-analysis for the symptom score and 18 for the medication score. In the direct pairwise meta-analysis, a significant reduction of the symptom score was observed for all immunotherapy modalities compared with the placebo: pooled SMDs of -0.461 (95% confidence interval [CI], -0.795 to -0.127) for SLIT drop, -0.329 (95% CI, -0.426 to -0.231) for SLIT tablet, and -1.669 (95% CI, -2.753 to -0.585) for SCIT. For the medication score, a significant reduction was observed for all modalities. In network meta-analysis, the clinical efficacy of SCIT based on the symptom score was greater than for SLIT drop or SLIT tablet (SMD: -0.697, 95% CI, -1.105 to -0.288; and SMD: -0.819, 95% CI, -1.242 to -0.397). However, there was no significant difference in the symptom score between SLIT drop and SLIT tablet. This study demonstrated the clinical efficacy of all house dust mite immunotherapy modalities and suggests that SCIT may be more effective than SLIT drops or tablets in controlling symptoms of allergic rhinitis.

Quickly evolving near-infrared photoimmunotherapy provides multifaceted approach to modern cancer treatment.

Among modalities of cancer immunotherapy, near-infrared photoimmunotherapy (NIR-PIT) has reached significant preclinical and clinical stages and quickly evolved over the last 5 years. NIR-PIT uses deep-penetrable NIR light to induce physicochemical changes in the antibody-photosensitizer conjugate (APC), leading to resultant necrosis and immunogenic cell death (ICD) of the cancer cells. Alternatively, other types of photomedicine use photosensitizers to convert absorbed light energy either into reactive oxygen species for photodynamic therapy (PDT) or into heat for photothermal therapy (PTT). ICD is a unique and relevant outcome of NIR-PIT because it induces long-lasting antitumor host immunity, which overcomes the immunosuppressive network of cancer. Due to its high specificity and durable antitumor effects, NIR-PIT is now considered a promising cancer therapy, and optimized NIR-PIT is readily expanding its applicability to many different types of cancer. Along with the traditional method of NIR-PIT, new avenues in its realm of treatment are currently being explored, such as the targeting of other immunosuppressive elements, delivery of NIR light through a catheter, real-time imaging for tumor detection, and the use of tumor-seeking small molecules for improved efficacy and safety. In addition, its effect on hyperpermeability has opened a door for a wide array of combination therapies with other modalities. This review summarizes the recent findings in clinical and preclinical studies of NIR-induced photomedicine and its future significance in the field of cancer research.