Immune Response In Combination Research Articles

Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer

BackgroundThe effectiveness of immune checkpoint inhibitors in colorectal cancer (CRC) is limited due to the low tumor neoantigen load and low immune infiltration in most microsatellite-stable (MSS) tumors. This study...

The equivalence of different types of electric pulses for electrochemotherapy with cisplatin - an in vitro study.

Electrochemotherapy (ECT) is a treatment involving the administration of chemotherapeutics drugs followed by the application of 8 square monopolar pulses of 100 μs duration at a repetition frequency of 1 Hz or 5000 Hz. However, there is increasing interest in using alternative types of pulses for ECT. The use of high-frequency short bipolar pulses has been shown to mitigate pain and muscle contractions. Conversely, the use of millisecond pulses is interesting when combining ECT with gene electrotransfer for the uptake of DNA-encoding proteins that stimulate the immune response with the aim of converting ECT from a local to systemic treatment. Therefore, the aim of this study was to investigate how alternative types of pulses affect the efficiency of the ECT. We performed in vitro experiments, exposing Chinese hamster ovary (CHO) cells to conventional ECT pulses, high-frequency bipolar pulses, and millisecond pulses in the presence of different concentrations of cisplatin. We determined cisplatin uptake by inductively coupled plasma mass spectrometry and cisplatin cytotoxicity by the clonogenic assay. We observed that the three tested types of pulses potentiate the uptake and cytotoxicity of cisplatin in an equivalent manner, provided that the electric field is properly adjusted for each pulse type. Furthermore, we quantified that the number of cisplatin molecules, resulting in the eradication of most cells, was 2-7 × 107 per cell. High-frequency bipolar pulses and millisecond pulses can potentially be used in ECT to reduce pain and muscle contraction and increase the effect of the immune response in combination with gene electrotransfer, respectively.

Facile manganese ion-coordination assembly of nanogels for synergistic cancer chemo–chemodynamic-immunotherapy

Metal-ion therapy is an emerging technique for cancer treatment, where anticancer metals trigger an immune response against tumor cells due to immunogenic cell death while enabling chemokinetic therapy, and the integration of these activities holds considerable anticancer potential for achieving high specificity and efficiency. Herein, we designed acid-responsive manganese-based nanogels with high drug-loading capacity for combined chemotherapy, chemodynamic therapy, and metal-immune therapy. The chemotherapeutic drug mitoxantrone, metallic manganese ions, and polymeric polyacrylic acid self-assembled into stable nanogels that could be efficiently internalized by cancer cells efficiently, releasing Mn2+ to catalyze highly toxic of hydroxyl generation from endogenous H2O2 and induce tumor cell apoptosis. Furthermore, the Mn2+-mediated activation of cyclic guanosine monophosphate adenosine synthetase activated the stimulator of interferon genes (STING) pathway, thereby inducing dendritic cell maturation. Following intravenous injection into immunocompetent tumor-bearing mice, the nanogels effectively exerted a tumor-killing effect and enhanced the antitumor immune response in combination with an aCTLA-4 antibody. Manganese ions also enhanced T1-weighted magnetic resonance imaging for integrated diagnosis and treatment. Overall, the manganese-based nanogel demonstrates significant synergistic efficacy through combined chemotherapy, chemodynamic therapy and metal-immune therapy, providing a versatile therapeutic strategy for cancer treatment.

IMMU-33. PRECISION ANTIGEN-DIRECTED IMMUNOTHERAPY TREATMENT OF BRAIN TUMORS INCREASES TUMOR-INFILTRATING EFFECTOR LYMPHOCYTE RESPONSES

Abstract BACKGROUND Despite considerable advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized tumor antigens expressed within brain tumors that can mediate tumor rejection; the limited mutational burden within these cancers that limits the abundance of targetable neoantigens; and the immunologically “cold” tumor microenvironment that hampers the generation of sustained and productive immunologic responses. Our OBJECTIVE is to develop a precision immunotherapy approach for brain tumor patients utilizing prospectively identified tumor-specific antigens using cancer immunogenomics and selective amplification of patients’ tumor-specific antigens for generating tumor antigen-specific lymphocyte therapy. METHODS We identified neoantigens and tumor-associated antigens that were uniquely expressed in preclinical glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (ORAN). A tumor antigen-specific RNA library was created for each tumor model and tumor-bearing animals were treated with ex vivo expanded tumor-specific lymphocytes and tumor antigen-specific RNA-loaded dendritic cell (tsRNA-DC) vaccines. In a different approach, animals were treated with a combination of tsRNA-DC vaccines and anti-PD-1 checkpoint-blockade therapy. Tumor progression and survival outcomes were determined. The immune cell response was evaluated using flow cytometry, TCR sequencing, and single-cell RNAseq. RESULTS Our results demonstrate the effectiveness of tsRNA-DC vaccines in eliciting robust anti-tumor immune responses in combination with adoptive cellular therapy and checkpoint blockade therapy. Additionally, our findings substantiate a robust increase in tumor-infiltrating lymphocytes characterized by enhanced effector function both intratumorally and systemically after tumor antigen-specific RNA-directed immunotherapies. CONCLUSION This powerful approach to generating immunotherapy recognizing a plurality of tumor antigens uniquely addresses the challenge of dealing with tumor antigenic heterogeneity and confronting the reality of patient-to-patient variation in antigen expression in the development of antigen targeting strategies.

Ferrocene-conjugated polymeric platform via amide bond formation facilitates enhanced in situ fenton reaction and robust immune responses in combination with toll-like receptor 7/8 agonist

Chemodynamic therapy (CDT) holds promise for catalyzing in situ Fenton/Fenton-like reactions by decomposing H2O2 to produce highly toxic hydroxyl radicals (•OH). As a CDT candidate, ferrocene (FcA)-based agents arouse extensive attention due to the stable divalent state of Fe2+. However, due to the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of small molecules, how to increase the accumulation of FcA at tumor sites while maintaining high catalytic efficiency is still challenging. Herein, we designed a polymeric platform (N@Fc) to increase the tumor accumulation of FcA and induce improved catalytic efficiency. The FcA was conjugated to the biocompatible polymer via an amide bond, which served as an electron donor for the FcA group, thereby leading to higher electron density and catalytic efficiency. In combination with polymeric conjugated TLR7/8 agonist (IMDQ), N@Fc/IM could prime adaptive antitumor immunity by activating antigen-presenting cells and enhance the infiltration of T lymphocytes, and thus boosting robust immune response.

Abstract 3281: GEN1042 (DuoBody-CD40x4-1BB)®in combination with PD-1 blockade reverses T-cell exhaustion in vitro

Abstract GEN1042 (DuoBody®-CD40x4-1BB) is an investigational, novel, agonistic, bispecific antibody that combines targeting and conditional activation of CD40 and 4-1BB on immune cells for priming and (re-) activation of tumor-specific immune responses. We previously showed that GEN1042 induces conditional CD40 and 4-1BB agonist activity, leading to dendritic-cell maturation and enhanced T-cell activation and effector functions in vitro. However, dysfunction of exhausted T cells in the solid tumor microenvironment may represent a potential resistance mechanism to checkpoint inhibitors/agonists. Here we utilized a multi-omics approach to evaluate whether GEN1042 could reverse T-cell exhaustion in vitro. Publicly available single cell RNA sequencing datasets were harmonized across multiple solid-tumor indications (including treatment-naïve and anti-PD-1 and/or anti-CTLA-4 pretreated samples) and analyzed for expression of CD40, 4-1BB and PD-1 on various immune-cell subsets based on their transcriptomic signatures to characterize target prevalence. In vitro mixed lymphocyte reaction (MLR) functional assays were performed where unstimulated healthy donor CD3+ T cells or CD3+ T cells exhausted by repeated stimulation with anti-CD3/CD28 beads were co-cultured with allogeneic lipopolysaccharide (LPS)-matured dendritic cells. Cultures were analyzed for cytokine secretion and expression of cell surface proteins. In the unstimulated T cell/mDC MLR assay, concurrent treatment with GEN1042 and PD-1 blockade potentiated IFNγ, TNFα and IL-2 production compared with either compound alone. In the T-cell exhaustion MLR assay, T cells showed increased expression of inhibitory receptors (e.g., TIM-3, LAG-3) and exhibited hyporesponsiveness for both proliferation and cytokine secretion upon restimulation with anti-CD3/CD28 beads. Here, the combined functional effect of GEN1042 plus PD-1 blockade further potentiated IFNγ secretion compared to single agent activity and induced IL-2 at similar levels to that observed for GEN1042 alone. These data suggest that, in addition to enhancing T-cell effector functions during T cell priming, GEN1042 can amplify the magnitude of the immune response in combination with PD-1 blockade by re-establishing the functional activity of dysfunctional T cells. GEN1042 is currently being evaluated in patients with advanced solid tumors in a phase 1/2 clinical trial (NCT04083599). Citation Format: Vanessa M. Spires, Gregg Masters, Christina Yu, Matt Hancock, Monique N. Luijten, Alexander Muik, Kristina Nuermberger, Friederike Gieseke, Tahamtan Ahmadi, Özlem Türeci, Maria Jure-Kunkel, Ugur Sahin, Mark Fereshteh, Homer C. Adams, Jordan M. Blum. GEN1042 (DuoBody-CD40x4-1BB)®in combination with PD-1 blockade reverses T-cell exhaustion in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3281.

Metabolic Barriers to Glioblastoma Immunotherapy.

Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients (glucose, glutamine, tryptophan, and lipids) has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism.

Difficulties of differential diagnosis of polyneuropathy developed after Gam-COVID-Vac vaccination on the background of combined infectious pathology (clinical case)

The clinical case describes the difficulties of differential diagnosis of polyneuropathy that developed after Gam-Covid-Vac vaccination on the background of combined infectious pathology (HIV infection, tick-borne borreliosis, COVID-19) in a young woman. It is shown that various infectious and non-infectious diseases with similar clinical symptoms (peripheral nervous system affliction) occurring simultaneously in one patient can significantly affect each other’s course and complicate the establishment of the true cause of polyneuropathy. It should be noted that in this example, the establishment of a final diagnosis was carried out collectively, by consensus, and was based on the effectiveness of etiotropic (antibacterial) treatment, which in fact was an ex juvantibus therapy option, which made it possible to establish the most probable etiology of polyneuropathy – tick-borne borreliosis. In turn, HIV infection and possibly vaccination, according to the authors, could cause immunosuppression, which affected the degree of dissemination of Borrelia burgdorferi. It is also likely that the insufficient immune response in combination with the cascade plasma filtration session affected the initial dubious results of the serological tests, which further complicated the diagnosis.

Zinc transporter LIV1: A promising cell surface target for triple negative breast cancer.

Breast cancer is one of the leading causes contributing to the global cancer burden. The triple negative breast cancer (TNBC) molecular subtype accounts for the most aggressive type. Despite progression in therapeutic options and prognosis in breast cancer treatment options, there remains a high rate of distant relapse. With advancements in understanding the role of zinc and zinc carriers in the prognosis and treatment of the disease, the scope of precision treatment/targeted therapy has been expanded. Zinc levels and zinc transporters play a vital role in maintaining cellular homeostasis, tumor surveillance, apoptosis, and immune function. This review focuses on the zinc transporter, LIV1, as an essential target for breast cancer prognosis and emerging treatment options. Previous studies give an insight into the role of LIV1 in fulfilling the most important hallmarks of cancer such as apoptosis, metastasis, invasion, and evading the immune system. Normal tissue expression of LIV1 is limited. Higher expression of LIV1 has been linked to Epithelial-Mesenchymal Transition, histological grade of cancer, and early node metastasis. LIV1 was found to be one of the attractive targets in the therapeutic hunt for TNBCs. TNBCs are an immunogenic breast cancer subtype. As zinc transporters are known to serve as the metabolic gatekeepers of immune cells, this review bridges tumor infiltrating lymphocytes, TNBC and LIV1. In addition, the suitability of LIV1 as an antibody-drug conjugate (Seattle genetics [SGN]-LIV1A) target in TNBC, represents a promising strategy for patients. Early clinical trial results reveal that this novel agent reduces tumor burden by inducing mitotic arrest, immunomodulation, and immunogenic cell death, warranting further investigation of SGN-LIV1A in combination with immuno-oncology agents. Priming the patient's immune response in combination with SGN-LIV1A could eventually change the landscape for the TNBC patient population.

Downregulation of exosomal MHC-I promotes glioma cells escaping from systemic immunosurveillance

Tumor-derived exosomes are capable of inducing immune dysfunction and favoring the formation and progression of tumor. The major histocompatibility complex class I (MHC-I) plays a key role in antitumor immune responses by presenting tumor antigens to cytotoxic T lymphocytes. However, the role of tumor-derived circulating exosomal MHC-I on immune system activation remains unclear. We demonstrated that low level of glioma cells-derived exosomal MHC-I was associated with the dysfunction of CD8+ T cells in immune activation and cytotoxicity. MHC-I upregulation in exosomes restored antigen presentation of glioma cells and activated CD8+ T cells to exert robust antitumor immune response in combination with immune checkpoint blockade. Collectively, these data provided evidences for an important interplay between exosomal MHC-I and CD8+ T cells to activate systemic antitumor immune response, and interpreted how glioma cells evaded immunosurveillance, induced immunosuppression and were resistant to immunotherapy from the perspective of systemic immunity.

Abstract 1304: Brachytherapy dose heterogeneity primes response to immune checkpoint blockade to generate anti-tumor immunity

Abstract Purpose: The immunologic effects of radiation (RT) are influenced by dose and each may be optimized over a unique dose range. We used brachytherapy (BT) to deliver a heterogeneous RT dose within a single tumor and compared the relative capacities of BT and homogenous dose external beam radiotherapy (EBRT) to enhance the anti-tumor immune response in combination with immune checkpoint inhibition (ICI). Materials and Methods: We used syngeneic murine models of melanoma (B78) and prostate cancer (Myc-CaP). To evaluate the effect of BT on the microenvironment, mice bearing B78 tumors were randomized to receive BT (192Ir source, 2 Gy to tumor edge), sham insertion, or EBRT (2, 8, or 20 Gy). Tumors were harvested 3 days following RT and in the case of BT, punch excisions were taken from the dissected tumor 1, 3, and 5 mm from the source location for gene expression and immune cell infiltration analysis. To evaluate anti-tumor response, we randomized mice bearing B78 tumors on the right flank (~200 mm3) and left shoulder (~100 mm3) to BT alone, catheter insertion alone, BT + ICI (anti-PD-L1 and anti-CTLA-4, 200 µg IP injection days 3, 6, 9 after RT), EBRT (2 or 8 Gy) + ICI, or ICI alone. Mice bearing MyC-CaP tumors were randomized to sham insertion, BT (2 or 8 Gy to tumor edge), BT + ICI, EBRT (2, 8, or 20 Gy) + ICI, or ICI alone. Immediately following RT, mice were engrafted with a secondary tumor. Results: Using qPCR analysis, we observed statistically significant differences in gene expression of Mhc-1, Ifnβ, and Vcam between tissue locations in BT treated tumors. Furthermore, in a single tumor BT optimally engaged all three pathways while each EBRT dose only optimally engaged one. Bulk RNAseq analysis revealed unique gene expression signatures between tissue locations in BT treated tumors. We observed significant differences in number of CD8+ and FOXP3+ cells between tissue locations. In B78 tumor bearing mice, we observed a greater anti-tumor response at the secondary untreated tumor with BT + ICI (63% CR) compared to EBRT + ICI (12.5% CR). In mice bearing Myc-CaP tumors treated with BT + ICI, we observed a significant reduction in tumor growth compared to other groups and no engraftment at the secondary tumor. This effect was dependent on both CD4+ and CD8+ cells and was sensitive to BT dose. Splenocytes harvested from disease-free mice co-cultured with tumor cells showed significant increases in expression of T cell activation markers in both CD4+ and CD8+ cell populations. Conclusions: We report dose-dependent effects of RT on expression of immune susceptibility markers and immune cell infiltration in a murine tumor model. We observe that a heterogeneous dose of BT results in spatial differences in these effects within a single tumor. This spatial heterogeneity in activation of immune mechanisms may underlie a greater capacity of BT to augment anti-tumor immune response when combined with ICI, as compared to homogenous dose EBRT. Citation Format: Justin C. Jagodinsky, Wonjong Jin, Jessica M. Vera, Raghava N. Sriramaneni, Paul A. Clark, Keng-Hsueh S. Lan, Ishan Chakravarty, Noah Siegel, Raad H. Allawi, Sarah E. Emma, Ian S. Arthur, Rupak K. Das, Irene M. Ong, Jessica R. Miller, Zachary S. Morris. Brachytherapy dose heterogeneity primes response to immune checkpoint blockade to generate anti-tumor immunity [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 1304.

Non-cytotoxic nanoparticles re-educating macrophages achieving both innate and adaptive immune responses for tumor therapy

Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity, while they are programmed to M2 phenotype in established tumors and instead promote cancer development and metastasis. Here, we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities. The nanomedicine has a core-shell structure to co-load IPI549, a PI3Kγ inhibitor, and CpG, a Toll-like receptor 9 agonist. Specifically, the hydrophobic IPI549 is self-assembled into a pure drug nano-core, while MOF shell layer is coated for CpG encapsulation, achieving extra-high total drugs loading of 44%. Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity, displaying excellent biocompatibility. After entering macrophages, the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype, which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines. Moreover, tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators, resulting in infiltration and activation of cytotoxic T lymphocytes. As a result, the nanosystem triggers a robust anti-tumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis. This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.

Blocking CD47 with restructured peptide nanoparticles for motivating phagocytosis to inhibit tumor progression.

Phagocytosis checkpoints, especially targeting CD47, have shown encouraging therapeutic effects. However, there are currently many shortcomings and challenges with immune checkpoint blockades (ICBs). Inspired by the phenomenon of molecular self-assembly, we modify the CD47 targeting peptide (4N1K) onto the self-assembled peptide FY4, as well as the concatenation of PEG at the other terminal via the AZO group to construct hypoxia-responsive nanoparticles (PEG-AZO-FY4-4N1K, PAP NPs), utilizing the peptide as a part of the anti-tumor therapy machine. After degradation, PAP NPs can self-assemble to form fibrous networks and anchor CD47 on the surface of tumor cells, promoting their recognition and phagocytosis by macrophages and relieving immune escape. Self-assembled peptides can interweave on the surface of tumor cells, fully exploiting their morphological advantages to impede normal cell interaction and metastasis. The PAP NPs work synergistically with Doxorubicin (DOX) to further maximize the efficacy of chemoimmunotherapy. In conclusion, this strategy pioneers the progress of self-assembled peptides in biomedicine and promises a novel breakthrough in the development of checkpoint inhibitor therapies.

P17.03 Sintilimab With Two Cycles Nab-Paclitaxel / Platinum as First Line Therapy for Advanced Squamous Non–Small-Cell Lung Cancer

Although immune checkpoint inhibitors (ICIs) in combination with chemotherapy has become the new stand of care in NSCLC, the optimal treatment cycles of chemotherapy is still debating. Chemotherapy is able to sensitize immune response in combination with ICIs via inducing tumor cell apoptosis and releasing neoantigen in initial combining cycles. In contrast, increasing cycles of chemotherapy might play negative roles of toxicity rather than synergetic effects. Therefore, this open-lable, multi-center, phase II study is to investigate the efficacy and safety of sintilimab in combination with short-course (two cycles) nab-paclitaxel / platinum in treatment naïve advanced squamous NSCLC patients.

Abstract 1715: First in class inhibitors of ERAP1 have the potential to be a transformative immunotherapy in oncology

Abstract Clinical data demonstrates increased antigen presentation diversity is an important factor in determining response rates to checkpoint inhibitors. In addition to tumor mutational burden, increased HLA heterozygosity and HLA evolutionary diversity are non-overlapping factors which further diversify the immunopeptidome and improve clinical response to checkpoint therapies. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides loaded into classical and nonclassical MHC Class I molecules. Human genome-wide association studies have identified single nucleotide polymorphisms within ERAP1 that are associated with immune-related diseases, such as ankylosing spondylitis, providing human genetic validation for ERAP1's role in human disease and antigen presentation. Further, ablation of mouse ERAAP modifies the immunopeptidome, resulting in improved immunogenicity, generation of CD8+ T cell responses and tumor growth inhibition. Grey Wolf Therapeutics have developed highly potent and selective ERAP1 inhibitors. These inhibitors demonstrate significant modulation of the cancer-related antigen repertoire across diverse ERAP1 and HLA genotypes and cancer-type backgrounds, both in vitro and in vivo. These changes in the antigen repertoire drive changes in T cell activation and response, leading to increased T cell infiltration into CT26 syngeneic tumors and T cell receptor (TCR) diversification when combined with anti-PD-1. We have identified immune related markers that are modulated following ERAP1 inhibition in syngeneic tumor models which have the potential to be used as biomarkers. Importantly, ERAP1 inhibitor induced immunopeptidome and T cell changes lead to significant tumor growth inhibition in syngeneic mouse models when combined with anti-PD-1. In parallel, we have demonstrated the ability of ERAP1 inhibitor induced novel cancer associated antigens to stimulate human CD8+ T cell responses. Extensive assessment of the potential of ERAP1 inhibitors to enhance tumor immune responses in combination with additional therapies (e.g. chemotherapy and radiotherapy), across different tumor microenvironments, is ongoing. These data provide the foundation from which we plan to explore the potential of our first-in-class ERAP1 inhibitor development candidate in the clinic. Citation Format: Andrew Leishman, Fergus Poynton, Nicola Ternette, Elisa Lori, Camila de Almeida, Henry Leonard, Emma Reeves, Edd James, Kristopher Clark, Carmen Tong, Jason Shiers, Martin Quibell, Peter Ian Joyce. First in class inhibitors of ERAP1 have the potential to be a transformative immunotherapy in oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1715.

PP13 Presentation Time: 3:30 PM: Brachytherapy Dose Heterogeneity Turns Cold Tumors Hot

Purpose: The immunologic effects of radiation (RT) are influenced by RT dose and each may be optimized over a unique dose range. We hypothesized that a heterogeneous dose of RT might thereby optimally engage multiple immune pathways and allow for greater immune activation compared to homogenous RT dose. We used brachytherapy (BT) to deliver a heterogeneous RT dose within a single tumor and we compared the relative capacities of BT and homogenous dose external beam radiotherapy (EBRT) to enhance the anti-tumor immune response in combination with immune checkpoint inhibition (ICI).

The path to find an HIV vaccine.

The path to find an HIV vaccine.

Abstract IA-014: Strategies to enhance the immunogenicity of radiation therapy

Abstract Radiation is an ideal partner to enhance cancer immunogenicity. In response to DNA damage, cytosolic DNA released from the nucleus and mitochondria activates sensors like cGAS/STING, leading to release of IFNβ, that recruits and activates BAFT3+ dendritic cells, for cross-presentation and cross-priming of CD8+ T cells (Deng L et al, Immunity 2014; Vanpouille-Box C et al, Nature Communications 2017; Yamazaki T et al, Nat Immunol. 2020 Aug 3). Radiation also increases the trafficking of activated CD8+ T cells by releasing CXCL16, a chemokine that binds to CXCR6 (Matsumura et al., J Immunol, 2008). Recent evidence has demonstrated how as part of DNA damage response to radiation, genes mutated in cancer are expressed, availing neoantigens to the patient’s immune system (Formenti S et al,Nature Medicine, 2018). By recruiting both the innate and adaptive immune response in combination with immune checkpoint blockade (ICB) radiation can convert the irradiated tumor into an in situ vaccine. While ongoing translational and clinical research is testing radiation immunogenicity with current immunotherapy, the focus of this presentation is on how to best apply the immunogenic effects in combination with standard systemic cancer therapies. Most standard cancer therapies also have relevant effects on the immune system (for example see Ameratunga M et al, Clin Cancer Res 2019): deciphering the immunological effects that accompany the cytocidal effects of available cancer therapies can guide their optimal integration. With regards to RT, the relevance to an immune response of selecting specific treatment fields, lymphatic sparing, specific radiation dose and fractionation as well as optimal sequencing iare rapidly emerging. For instance, in the setting of metastatic disease, cancer heterogeneity (De Mattos-Arruda L, et al. Cell, 2019) requires radiation targeting of all detectable metastatic deposits. A multi-institutional Canadian trial on oligometastatic cancer patients (with up to 5 metastases) has demonstrated a promising improvement in time-to-progression and survival after stereotactic body radiotherapy (SBRT) to each metastasis (Palma DA et al, Lancet, 2019). In addition to targeting heterogeneity, maximal reduction of tumor burden by multi-site SBRT can enable an immunological equilibrium and potentially prolong survival. Conversely, preclinical evidence discourages the inclusion of draining nodal stations in the field of radiotherapy (Marciscano A et al, Clin Cancer Res; 2018). Finally, data about the optimal timing of integration of SBRT with systemic therapy will be presented, by describing the example of oligometastatic ER+ breast cancer. The preclinical results of different sequencing of focal radiation with with CDK4/6 inhibitors and endocrine therapy in a murine model of ER+ breast cancer will be presented (Petroni G. et al, Clinical Cancer Research, in press), as well as the emerging evidence for the type of selective remodeling of TME that radiotherapy induces when given before this systemic therapy combination. Citation Format: Silvia C. Formenti. Strategies to enhance the immunogenicity of radiation therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-014.

Rational Vaccine Design in Times of Emerging Diseases: The Critical Choices of Immunological Correlates of Protection, Vaccine Antigen and Immunomodulation.

Vaccines are the most effective medical intervention due to their continual success in preventing infections and improving mortality worldwide. Early vaccines were developed empirically however, rational design of vaccines can allow us to optimise their efficacy, by tailoring the immune response. Establishing the immune correlates of protection greatly informs the rational design of vaccines. This facilitates the selection of the best vaccine antigens and the most appropriate vaccine adjuvant to generate optimal memory immune T cell and B cell responses. This review outlines the range of vaccine types that are currently authorised and those under development. We outline the optimal immunological correlates of protection that can be targeted. Finally we review approaches to rational antigen selection and rational vaccine adjuvant design. Harnessing current knowledge on protective immune responses in combination with critical vaccine components is imperative to the prevention of future life-threatening diseases.

The Potentiation of Anti-Tumor Immunity by Tumor Abolition with Alpha Particles, Protons, or Carbon Ion Radiation and Its Enforcement by Combination with Immunoadjuvants or Inhibitors of Immune Suppressor Cells and Checkpoint Molecules.

The delivery of radiation therapy (RT) for cancer with intent to cure has been optimized and standardized over the last 80 years. Both preclinical and clinical work emphasized the observation that radiation destroys the tumor and exposes its components to the immune response in a mode that facilitates the induction of anti-tumor immunity or reinforces such a response. External beam photon radiation is the most prevalent in situ abolition treatment, and its use exposed the “abscopal effect”. Particle radiotherapy (PRT), which has been in various stages of research and development for 70 years, is today available for the treatment of patients in the form of alpha particles, proton, or carbon ion radiotherapy. Charged particle radiotherapy is based on the acceleration of charged species, such as protons or carbon-12, which deposit their energy in the treated tumor and have a higher relative biological effectiveness compared with photon radiation. In this review, we will bring evidence that alpha particles, proton, or carbon ion radiation can destroy tumors and activate specific anti-tumor immune responses. Radiation may also directly affect the distribution and function of immune cells such as T cells, regulatory T cells, and mononuclear phagocytes. Tumor abolition by radiation can trigger an immune response against the tumor. However, abolition alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement abolition to reinforce the anti-tumor immunity to better eradicate residual local and metastatic tumor cells. Various methods and agents such as immunoadjuvants, suppressor cell inhibitors, or checkpoint inhibitors were used to manipulate the immune response in combination with radiation. This review deals with the manifestations of particle-mediated radiotherapy and its correlation with immunotherapy of cancer.