Impact Of Immunotherapy Research Articles

The impact of immunotherapy in the treatment of solid tumors. What we found under 2021 Christmas tree

The treatment of solid tumors sees an increasing use of immune checkpoint inhibitors (anti PD-1/PDL-1, anti CTLA-4). The new drug combinations have revolutionized the treatment of different types of cancer, from melanoma to chest neoplasms, renal and esophageal cancer. All of these different diseases have one common denominator: the immune system. Only the immune system, properly stimulated, can attack and destroy different types of cancer, as if they were an infection. This review describes the most important milestones achieved in 2021 by combination treatment with immune checkpoint inhibitors.

Abstract IA07: Impact of immunotherapy on COVID-19 immunity: Insights from checkpoint blockade in cancer

Abstract Over the last few years, we have gained insights into how immunotherapy, including checkpoint blockade, modulates key CD4 and CD8 T cell subsets in anti-tumor immunity. This information can now give us insights into how immunotherapy can impact immunity in the setting of COVID-19. Indeed, we recently demonstrated that cancer patients with T cell depletion have high COVID-19 mortality despite adequate B cell and antibody production, highlighting the importance of cellular immunity. Conversely, in the setting of B cell depletion by anti-CD20 therapy, CD8 T cells can compensate for impaired humoral immunity. PD-1 blockade increases the activation and proliferation of CD4 T follicular-helper cells, which plays a key role in promoting B cell responses and quality antibody production. Thus, it is possible that PD-1 blockade enhances the efficacy of SARS-CoV-2 vaccination. However, PD-1 blockade in melanoma patients was actually associated with at 2-fold decrease in SARS-CoV-2 specific antibodies and neutralizing antibodies, compared to a healthy donor cohort. PD-1 blockade was also associated with depletion of memory CD4 T cells, suggesting there may be consequences to prolonged PD-1 blockade. Citation Format: Paulina Coutifaris, Kevin Wang, Sokratis Apostolidis, Mark Painter, Ahron Flowers, Rishi Goel, Divij Mathew, Ajinkya Pattekar, Ravi Amaravadi, Tara Mitchell, Paul Bates, Scott Hensley, Giorgos Karakousis, Lynn Schuchter, Allie Greenplate, E. John Wherry, Alexander C. Huang. Impact of immunotherapy on COVID-19 immunity: Insights from checkpoint blockade in cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA07.

Molecular therapeutic targets for cholangiocarcinoma: Present challenges and future possibilities.

A diagnosis of cholangiocarcinoma (CCA) is implicit with poor prognosis and limited treatment options, underscoring the near equivalence of incidence and mortality rates in this disease. In less than 9years from genomic identification to FDA-approval of the corresponding inhibitors, fibroblast growth factor receptor 2 (FGFR2) rearrangements and isocitrate dehydrogenase 1 (IDH1) mutations became exemplary successes of precision oncology in subsets of patients with CCA. However, clinical trial results from multikinase inhibitors in unselected populations have been less successful, while the impact of immunotherapies are only beginning to impact this setting. Development of future therapeutics is incumbent with new challenges. Many driver alterations occur in tumor suppressor-like genes which are not directly druggable. Therapeutically, this will require identification of ensuant "non-oncogene addiction" involving genes which are not themselves oncogenes but become tumor survival dependencies when a specific driver alteration occurs. The low recurrence frequency of genomic alterations between CCA patients will require careful evaluation of targeted agents in biomarker-enrolled trials, including basket trial settings. Systematic expansion of candidate drug targets must integrate genes affected by non-genetic alterations which incorporates the fundamental contribution of the microenvironment and immune system to treatment response, disease facets which have been traditionally overlooked by DNA-centric analyses. As treatment resistance is an inevitability in advanced disease, resistance mechanisms require characterization to guide the development of combination therapies to increase the duration of clinical benefit. Patient-focused clinical, technological and analytical synergy is needed to deliver future solutions to these present therapeutic challenges.

Impact of the allergen-specific immunotherapy in pediatric patients with asthma treated at a health institution in Colombia

ResumenIntroducción. El asma es una enfermedad crónica y potencialmente grave. El 80 % de los casos es de origen alérgico, por lo cual la inmunoterapia específica con alérgenos es una alternativa terapéutica que modula el curso natural de la enfermedad. Objetivo. Evaluar el impacto de la inmunoterapia en pacientes pediátricos con asma atendidos en una institución de salud de Colombia.Materiales y métodos. Se hizo un estudio observacional descriptivo con componente analítico de corte transversal. Se incluyeron 62 pacientes con diagnóstico de asma alérgica sensibilizados a ácaros del polvo y en tratamiento, mínimo, con seis dosis de inmunoterapia contra ácaros. El efecto del tratamiento se evaluó mediante la escala de puntuación del ACT (Asthma Control Test), la escala de tratamiento de la GINA (Global Initiative for Asthma) y la espirometría.Resultados. La puntuación de la prueba ACT antes del inicio de la inmunoterapia, correspondía a 30 % de pacientes con asma no controlada, 28 % con buen control y 4 % con asma totalmente controlada. Entre los pacientes con asma no controlada, el 46,7 % logró un buen control y el 23,3 % alcanzó un control total. En cuanto a la percepción de los pacientes sobre la mejoría con la inmunoterapia, el 9,75 % percibió una mejoría menor del 50 %, el 45,2 %, una entre el 50 y el 90 %, en tanto que el 41,9 % refirió una igual o mayor del 90 %. No se encontraron cambios significativos en los valores del volumen espiratorio forzado en un segundo (VEF1) en las espirometrías.Conclusiones. Se observaron cambios significativos en los puntajes del ACT y en la percepción de mejoría de la enfermedad en la población tratada con inmunoterapia específica para ácaros, es decir, que esta tendría un efecto beneficioso en el curso natural de la enfermedad

The impact of immunotherapy on a glioma immune interaction model

Glioblastoma, a highly aggressive in primary brain tumor and has exceptionally poor prognosis, is refractory to conventional treatments, such as chemotherapy, surgery and radiation. This study aims at aiding in the design of more successful glioma therapy. To understand the dynamics under what circumstances the glioma cells can be eradicated, we propose and analyze a mechanistic model for malignant gliomas and immune system interplays that may ensue upon direct intra-tumoral administration of immunotherapeutic agent T11 target structure. Our mathematical model encompasses considerations of the interactive dynamics of glioma cells, glioma-specific CD8+T cells, macrophages, immuno-suppressive cytokine TGF-β and immuno-stimulatory cytokine IFN-γ. The proposed mathematical model successfully retrieved clinical response to the immunotherapeutic drug T11 target structure for glioma cells. Our model enables us to identify the treatment regimen for a determined time window, in order to obtain an admissible concentration of glioma cell population. To mathematically model the dynamics of malignant gliomas development, before and after administration of immunotherapeutic treatment strategy, we derived the local asymptotic stability for the biologically feasible equilibrium points and the local relative controllability conditions for this coupled system of nonlinear ordinary differential equations. The system undergoes sensitivity analysis to identify the most sensitive parameters with respect to glioma cells. Numerical simulations were conducted for model verification and for retrieving putative treatment scenarios. The model simulations suggest that the immunotherapy has an impact in reducing the growth of glioma cell population and also an impact in enhancing the cell count of macrophages and CD8+T cell populations.

Outcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients With Brain Metastases.

The impact of immunotherapy and stereotactic radiosurgery (SRS) in treatment of brain metastases (BM) from renal cell carcinoma (RCC) has not been well investigated. Forty-eight patients with 372 RCC BM were treated with SRS and divided into those ever treated with immunotherapy versus those who never received immunotherapy. Survival and local control (LC) outcomes were studied. χ2 and Mann-Whitney U tests compared categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival and log-rank test was used to compare survival between groups. Immunotherapy and nonimmunotherapy groups contained 29 and 19 patients, respectively. Median follow-up was 23.1 months (range, 6 to 93.8 mo). Demographic and treatment variables were similar except median prescribed margin dose was significantly lower in immunotherapy group (20 vs. 22 Gy, P<0.0001). Median overall survival (OS) was 27.2 months (immunotherapy) and 14.9 months (nonimmunotherapy), P=0.14. Furthermore, patients treated with immune checkpoint inhibitor (ICI) had even better median OS compared with those who never received ICI (33 vs. 16.7 mo, P=0.03). Factors associated with improved LC were use of ICI (P=0.002) and lesion size <1000 mm3 (P=0.046). There was no difference in incidence of radiation necrosis between the 2 groups (P=0.67). Patients with RCC BM undergoing SRS can experience prolonged survival when treated with ICI. Equally effective LC of BM was achieved when treated with immunotherapy using a 2 Gy decrease in SRS dose without increasing the risk of central nervous system toxicity.

Impact of immunotherapy on survival differences in patients with melanoma and chronic lymphocytic leukemia.

e21550 Background: Chronic lymphocytic leukemia (CLL) is well known to be associated with secondary malignancies like melanoma. Patients with melanoma and CLL are known to have poorer prognosis compared to patients without CLL. Checkpoint inhibitors (CPI) started gaining traction in 2011 after ipilimumab approval and are widely used in treatment of advanced melanoma. The objective of this study is to determine the survival of patients with melanoma and CLL in the era of CPI (2011 onwards) compared to previous years. Methods: We identified patients with melanoma and CLL reported to the Surveillance, Epidemiology, and End Results (SEER-18) program. We created cohorts of patients with melanoma and CLL vs. melanoma without CLL and split the cohorts into patients diagnosed from 2000-2010 and 2011-2017 to evaluate the impact of immunotherapy on overall all-cause survival. Kaplain-Meier survival curves were created for each of the four cohorts using the Ederer/direct-adjusted survival method. Standard Cox regression models adjusted for age and sex used to compare survival between subgroups. Two-sided p-values &lt; 0.05 were considered significant. Results: From 2000-2017, 536,264 patients with melanoma were included in this study. 2,945 [0.55%] patients had coexisting CLL. Most patients were male (303,477 [56.6%]), age 60-79 (235,833 [44.0%]), non-Hispanic white (499,151 [93.08%]), and diagnosed from 2000-2010 (285,292 [53.2%]) with melanoma of the trunk (156,722 [29.2%]). From 2000-2010, patients with melanoma had an average survival of 91.4 months (95% CI 88.7-94.1) and those with coexisting CLL had an average survival of 59.3 months (95% CI 58.1-60.6). From 2011-2017, patients with melanoma had an average survival of 129.1 months (95% CI 127.7-130.5) and those with coexisting CLL had an average survival of 116.0 months (95% CI 113.5-118.5). The difference in survival in patients with melanoma vs. melanoma and CLL in 2000-2010 (32.1 months) is significantly greater than that of patients from 2011-2017 (13.1 months, p &lt; 0.05). Conclusions: Although CLL continues to confer a survival disadvantage in patients with melanoma, the survival of patients with CLL and melanoma is better in the CPI-era. We also demonstrate that in the CPI era the gap between the survival of patients with melanoma and CLL and melanoma alone is also reducing significantly.

Impact of Immunotherapy on CD4 T Cell Phenotypes and Function in Cancer.

Immunotherapy has become a standard treatment in many cancers and it is based on three main therapeutic axes: immune checkpoint blockade (ICB), vaccination and adoptive cell transfer (ACT). If originally these therapies mainly focused on exploiting CD8 T cells given their role in the direct elimination of tumor cells, increasing evidence highlights the crucial role CD4 T cells play in the antitumor immune response. Indeed, these cells can profoundly modulate the tumor microenvironment (TME) by secreting different types of cytokine or by directly eliminating cancer cells. In this review, we describe how different CD4 T cell subsets can contribute to tumor immune responses during immunotherapy and the novel high-throughput immune monitoring tools that are expected to facilitate the study of CD4 T cells, at antigen-specific and single cell level, thus accelerating bench-to-bed translational research in cancer.

Bronchial Asthma and Lung Cancer

Aim: The aim of the study was to present existing evidence regarding the association between bronchial asthma and lung cancer risk, the impact of lung cancer treatment on asthma control as well as the impact of pre-existing asthma on lung cancer survival. Methods: A narrative review of all the relevant published literature has been conducted. Results: Published evidence suggests that patients with bronchial asthma are at a higher risk of developing lung cancer with an estimated odds ratio for squamous and small cell lung carcinoma at 1.69 and 1.71, respectively, within 2 years of asthma diagnosis. Interestingly, regular use of inhaled corticosteroids may protect asthmatics against lung cancer. Chemotherapy may temporarily relieve asthma symptoms. Pneumonitis is a common adverse reaction in asthmatics receiving immunotherapy for lung cancer treatment. Lung radiotherapy in asthma patients predisposes to eosinophilic alveolitis and pneumonia. Asthmatics are considered high-risk candidates for invasive surgical procedures because they carry a high risk of perioperative airway hyper responsiveness. Asthma is associated with a reduced lung cancer survival compared to other pulmonary co-morbidities. Conclusion: Literature shows that bronchial asthma is associated with increased lung cancer risk and worse survival rates. Chemotherapy may relieve asthma symptoms. However, asthmatics are prone to complications related to lung cancer surgery or radiotherapy treatment. Μore randomised controlled studies are required to strengthen the positive association between bronchial asthma and lung cancer, taking into consideration that there may be confounders that may influence the results. Finally, further studies must be conducted to investigate the impact of immunotherapy and specific radiotherapy modalities on asthma control.

A multicenter, retrospective study on impact of immunotherapy in urothelial carcinoma with bone metastases (Meet-Uro01 Study).

401 Background: Considerable numbers of patients (pts) with metastatic urothelial carcinoma (mUC) (approximately 25-47%) develop bone metastases (BoM). Their impact on the efficacy of immunotherapy (IO) is not yet sufficiently investigated. We developed a national collaboration on this issue, with the aim to assess the effect of BoM on survival outcomes of immunotherapy-treated pts in a large retrospective cohort. Methods: Data on pts diagnosed with mUC and treated between 07/14 and 08/20 with single-agent immunotherapy (IO) after failure of at least 1 previous line of chemotherapy (CT) for advanced disease, or (neo-)adjuvant CT within 12 months were retrospectively collected across 14 centers. PFS and OS were analyzed using the Kaplan-Meier method. Cox regression analysis was performed evaluating potential prognostic factors for OS and PFS. Each factor was evaluated in univariable (UV) and multivariable (MVA) analysis. Results: A total of 208 evaluable pts treated with single-agent immunotherapy (anti PD-1 n=42; anti PD-L1 n=166) were identified, including 122 without BoM (59% BoM-) and 86 (41%) BoM+. 13% of pts had progressed within 12 months after (neo-)adjuvant CT and 79% after a previous line of platinum-based CT for advanced disease (cisplatin 42.8%; carboplatin 36.5%). The presence of BoM negatively affected performance status (PS) of patients at baseline (ECOG PS 0/1/2 in 58% / 37% / 5% in BoM- vs 38% / 52% / 9% in BoM+; p=0.017). Other baseline characteristics were comparable. BoM+ showed shorter PFS (median 2.0 vs 2.6 months, HR 1.76 [95%CI, 1.31-2.37], p&lt;0.001) and OS (median 3.9 vs 7.8 months, HR 1.59 [95%CI, 1.15-2.20], p=0.005) than BoM-. Probability of being alive was 62% vs 40% after 6 months, 38% vs 23% after 1 year and 24% vs 13% after 2 years, in BoM- and BoM+ respectively. Within each Bellmunt score, PFS and OS of BoM+ pts were shorter compared to BoM-. Both BoM and higher Bellmunt risk score were significantly associated with shorter PFS and OS in UV and MV analyses (Table). Conclusions: Patients with mUC treated with single-agent immunotherapy for BoM+ advanced disease have a dismal prognosis compared with BoM-. Further research is needed to understand the mechanism behind these clinical outcomes. [Table: see text]

Immunotherapy for Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive form of skin cancer which, while chemosensitive, has high rates of relapse and chemoresistance, limiting the impact of chemotherapy. An immunogenic tumor, the management of advanced MCC has changed dramatically with the introduction of checkpoint inhibitors. This review will focus on the impact of immunotherapy in unresectable and metastatic MCC, ongoing research in the adjuvant and neoadjuvant settings, and future directions of immune-based strategies for this challenging cancer.

The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis: impact of immunotherapies.

Epstein–Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3‐expressing B cells preferentially infiltrate the CNS of MS patients. In chronic virus‐infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B‐cell subsets from MS patients who received autologous bone marrow transplantation (n = 9), which is often accompanied by EBV reactivation. The frequencies of nonclass‐switched and class‐switched memory B cells were reduced at 3–7 months, while only class‐switched B cells returned back to baseline at 24–36 months posttransplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+, and not CXCR4+ or CXCR5+, class‐switched B cells. Second, for CXCR3+ memory B cells trapped within the blood of MS patients treated with natalizumab (anti‐VLA‐4 antibody n = 15), latent EBV infection corresponded to enhanced in vitro formation of anti‐EBNA1 IgG‐secreting plasma cells under GC‐like conditions. These findings imply that EBV persistence in B cells potentiates brain‐homing and antibody‐producing CXCR3+ subsets in MS.

Molecular Immunotherapy: Promising Approach to Treat Metastatic Colorectal Cancer by Targeting Resistant Cancer Cells or Cancer Stem Cells.

The immune system is able to recognize and eliminate tumor cells. Some tumors, including colorectal cancer (CRC), induce immune tolerance via different mechanisms of “immunoediting” and “immune evasion” and can thus escape immune surveillance. The impact of immunotherapy on cancer has been investigated for many years, but so far, the application was limited to few cancer types. Immuno-oncological therapeutic strategies against metastatic colorectal cancer (mCRC), the adaptive immune system activating approaches, offer a high potential for adaptation to the great heterogeneity of CRC. Moreover, novel treatment approaches are currently being tested that might specifically target the disease initiating and maintaining population of colorectal cancer stem cells (CSCs). In this review, we aim to summarize the current state of immune-oncology and tumor immunotherapy of patients with mCRC and discuss different therapeutic modalities that focus on the activation of tumor-specific T-cells and their perspectives such as tumor vaccination, checkpoint inhibition, and adoptive T-cell transfer or on the eradication of colorectal CSCs.

An Italian Retrospective Survey on Bone Metastasis in Melanoma: Impact of Immunotherapy and Radiotherapy on Survival.

BackgroundWe performed a multicenter retrospective observational study to investigate the impact of clinical–pathological features and therapeutic strategies on both the complications and survival of patients with bone metastases (BMs) from malignant melanoma.Patients and MethodsA total of 305 patients with melanoma and radiological evidence of BMs were retrospectively enrolled from 19 Italian centers. All patients received conventional treatments in accordance with each own treating physician’s practice. Both univariate and multivariate models were used to explore the impact of melanoma features, including skeletal-related events (SREs), and different treatments on both overall survival (OS) and time-to-SREs. The chi-squared test evaluated the suitability of several parameters to predict the occurrence of SREs.ResultsEighty-three percent of patients had metachronous BMs. The prevalent (90%) bone metastatic site was the spine, while 45% had involvement of the appendicular skeleton. Forty-seven percent experienced at least one SRE, including palliative radiotherapy (RT) in 37% of cases. No melanoma-associated factor was predictive of the development of SREs, although patients receiving early treatment with bone-targeted agents showed 62% lower risk and delayed time of SRE occurrence. Median OS from the diagnosis of bone metastasis was 10.7 months. The multivariate analysis revealed as independent prognostic factors the number of BMs, number of metastatic organs, baseline lactate dehydrogenase levels, and treatment with targeted therapy or immunotherapy. Subgroup analyses showed the best OS (median = 16.5 months) in the subset of patients receiving both immunotherapy and palliative RT.ConclusionBased on our results, patients undergoing immunotherapy and palliative RT showed an OS benefit suggestive of a possible additive effect. The apparent protective role of bone targeting agent use on SREs observed in our analysis should deserve prospective evaluation.

135: A Population - Based Study on Radiation Therapy for Brain Metastasis From Malignant Melanoma in British Columbia: Evaluating The Impact of Immunotherapy and Stereotactic Techniques

135: A Population - Based Study on Radiation Therapy for Brain Metastasis From Malignant Melanoma in British Columbia: Evaluating The Impact of Immunotherapy and Stereotactic Techniques

Abstract 3874: Monitoring immune-tumor cell interactions in 3D microfluidic models with optical metabolic imaging and molecular profiling

Abstract The tumor microenvironment is defined by nutrient starvation, waste product accumulation, hypoxia, and acidosis, which collectively contribute towards immune exhaustion and suppression. Models that mimic the tumor microenvironment will be instrumental to develop new therapies that improve immune response. Microfluidic models can mimic the tumor metabolic microenvironment to elucidate mechanisms that lead to weakened tumor immunity and to new tumor immunotherapies. We developed microfluidic models where cancer cells were cultured as a dense mass embedded in a 3D matrix. The microfluidic platform has lateral channels that are lined with endothelial cells to mimic the tumor vasculature. These vessels can be perfused with immune cells or drugs that extravasate into the tumor mass. Immune cells were isolated from the tumor mass within these microfluidic models and gene expression was analyzed to quantify changes in immune cell function under tumor metabolic microenvironment conditions. Optical metabolic imaging of NADH and FAD autofluorescence with 2-photon microscopy monitored metabolic dynamics during tumor-immune cell interactions. Immunotherapy drugs were also perfused through the microfluidic devices to measure drug efficacy. Changes in immune cell function after drug exposure were analyzed by optical metabolic imaging to examine metabolic dynamics, alongside fluorescence microscopy to visualize cytotoxicity changes. Natural killer cells exhibited directional migration towards the tumor, which indicates that natural killer cells can detect the presence of the tumor several hundreds of microns away. Real-time microscopy revealed that natural killer cells destroyed tumor cells at the tumor periphery and notably at the innermost tumor core. Gene expression analysis of immune cells and tumor cells cultured in the microfluidic model reveals that the tumor cells have created an environment consistent with immunosuppression, immune exhaustion, and nutrient starvation. Metabolic imaging reveals that immune cells exposed to the tumor microenvironment have an altered metabolic profile, specifically decreased redox ratio that persists even under normal culture conditions. The microfluidic model provides a system to examine immune cytotoxicity, metabolic dynamics during tumor-immune interactions, and the impact of immunotherapies in enhancing immune cytotoxicity. Optical metabolic imaging and microfluidic models provide novel insight into metabolic dynamics with tumor cell and immune cell interactions within the tumor metabolic microenvironment. Future studies will expand this technology towards studying immune exhaustion and dysfunction in other immune therapies. Citation Format: Shujah H. Rehman, Jose M. Ayuso, Maria Maria Virumbrales-Munoz, Patrick H. McMinn, David J. Beebe, Melissa C. Skala. Monitoring immune-tumor cell interactions in 3D microfluidic models with optical metabolic imaging and molecular profiling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3874.

Abstract 5511: Frontline therapy with anti-PD1 enhances the durability of combination targeted therapy in NRAS-mutant melanoma

Abstract Melanoma is one of the deadliest form of skin cancer. Although the activating NRAS mutations are present in 20% of melanoma patients, currently, there are no FDA-approved therapies for treating NRAS-mutant melanoma. In this project, our goal is to prime the immune system by immunotherapy and then improve the targeted therapy responses by suppressing recruitment of inhibitory immune cell populations and by increasing T cell infiltration, which would lead to enhanced responses in NRAS-mutant melanoma. We used a syngeneic C3H/HeNCrl mouse model of NRAS-mutant melanoma. The mice were treated with two doses of either anti-PD1 or IgG every 5 days followed by everyday treatment with either single agent or combination of ceritinib and trametinib for a total period of 40 days. Single cell RNA-seq platform was used to determine the impact of immunotherapy and targeted therapy upon each individual cell type. Flow cytometry experiments were carried out to assess the percentage of T cells and MDSCs recruitment. Altered signaling responses and chemokines/ cytokines responsible for MDSCs recruitment were determined from RPPA and RNA-seq data respectively. The in vivo studies demonstrated that the tumors in the mice treated with anti-PD1 followed by combination shrunk significantly over a period of 40 days without any relapse. Single cell RNA seq analysis and flow cytometry experiments revealed a 15- and 20-fold increase in T cell infiltration in these tumors. Immune cells depletion experiments showed that the cytotoxic effects of combination therapy was dependent upon CD8+ T cells only. Single cell RNA seq analysis also demonstrated that priming with immunotherapy increased IFN γ expression on T cells and subsequent treatment with ceritinib+trametinib increased melanoma antigen presentation by increased MHC class I expression. The RPPA data from tumors treated with anti-PD-1 followed by combination demonstrated inhibition of RTKs implicated in therapy escape such as c-MET, EGFR, IGF1R, HER2/3. Flow cytometric analysis also revealed around 60% decrease in Tregs and 80% decrease in MDSCs recruitment in the tumors treated with anti-PD1 followed by combination. RNA seq analysis revealed that ceritinib decreased mRNA expression of cytokines/ chemokines such as Cxcl5, Cxcl3, Cxcl2, Csf1, Cx3cl1, Cklf, that have been implicated in the recruitment and differentiation of MDSCs. Hence, we demonstrate that frontline immunotherapy primes the immune system, making the tumors more immunogenic with an increased accumulation of activated CD8+ T cells. Successive treatment with combination targeted therapy not only increases antigen presentation to T cells but also decreases recruitment of immunosuppressive MDSCs thus preventing immune escape and tumor progression. In summary, we have developed novel targeted therapy combinations that can be sequentially used with immunotherapy to maximize the durations of response in treatment of NRAS-mutant melanoma. Citation Format: Manali S. Phadke, Zhihua Chen, Eslam Mohamed, Michael Davies, Ann Chen, Uwe Rix, Paulo Rodriguez, Keiran Smalley. Frontline therapy with anti-PD1 enhances the durability of combination targeted therapy in NRAS-mutant melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5511.

Impact of Immunotherapy on the Survival of Patients With Cancer and Brain Metastases

Background: Immunotherapy has shown excellent efficacy in various cancers. However, there is a lack of knowledge regarding the significant role of immunotherapy in patients with brain metastases (BMs). The objective of this study was to investigate, using the National Cancer Database, the impact of immunotherapy on the overall survival (OS) of patients with BMs who did not receive definitive surgery of the primary tumor. Patients and Methods: Patients diagnosed with the primary cancer of non–small cell lung cancer, small cell lung cancer, other types of lung cancer, breast cancer, melanoma, colorectal cancer, or renal cancer who had BMs at the time of diagnosis were identified from the National Cancer Database. We assessed OS using a Cox proportional hazards model adjusted for age at diagnosis, sex, race, education level, income level, residential area, treatment facility type, insurance status, Charlson-Deyo comorbidity status, year of diagnosis, primary tumor type, and receipt of chemotherapy, radiation therapy (RT), and/or immunotherapy, because these factors were significantly associated with OS in the univariable analysis. Results: Of 94,215 patients who were analyzed, 3,097 (3.29%) received immunotherapy. In the multivariable analysis, immunotherapy was associated with significantly improved OS (hazard ratio [HR], 0.694; 95% CI, 0.664–0.726; P&lt;.0001) compared with no immunotherapy. Treatment using chemotherapy plus immunotherapy was significantly associated with improved OS (HR, 0.643; 95% CI, 0.560–0.738; P&lt;.0001) compared with chemotherapy without immunotherapy. RT plus immunotherapy was also associated with significantly improved OS (HR, 0.389; 95% CI, 0.352–0.429; P&lt;.0001) compared with RT alone. Furthermore, chemoradiation (CRT) plus immunotherapy was associated with significantly improved OS (HR, 0.793; 95% CI, 0.752–0.836; P&lt;.0001) compared with CRT alone. Conclusions: In this comprehensive analysis, the addition of immunotherapy to chemotherapy, RT, and CRT was associated with significantly improved OS in patients with BMs. The study warrants future clinical trials of immunotherapy in patients with BMs, who have historically been excluded from these trials.

476 Utilization and impact of immunotherapy in stage IV melanoma using the National Cancer Database

The majority of data regarding immunotherapy for melanoma stems from trials that exclude important populations. Thus, while trials may demonstrate favorable results, not all populations may be represented. To evaluate factors affecting the utilization of immunotherapy and to stratify results based on the approval of ipilimumab in 2011 and PD-1 inhibitors in 2014, an analysis of available data from the National Cancer Database (NCDB) was performed. Stage IV melanoma patients were identified. Effects of immunotherapy on overall survival (OS) were assessed using Kaplan Meier curves and Cox proportional hazards model. 19,233 patients were analyzed, of whom, 1,998 received immunotherapy. Between 2011-2013, and in 2014, 18.6% and 28.9% of patients received immunotherapy, respectively. Younger patients and those with fewer co-morbidities or receiving care in an academic institution were more likely to receive immunotherapy. Patients without insurance were less likely to receive immunotherapy. Patients who received immunotherapy from 2011-2013 had a 33% (95% CI 30-35%) 3-year OS compared to 23% (95% CI 21-24%) for those who did not. In 2014, 3-year OS was 37% (95% CI 32-43%) for those who received immunotherapy compared to 22% (95% CI 18-26%) for those who did not (log-rank p<0.0001). This is the first analysis of a large cancer database for patients with any cancer with stratification of results based on utilization and availability of immunotherapy. Immunotherapy utilization increased yearly and improved OS. With combination immunotherapy now more widely employed, it is expected these results will continue to improve.

The impact of neoadjuvant and adjuvant immunotherapy on the survival of pancreatic cancer patients: a retrospective analysis

BackgroundImmunotherapy has become an essential part of cancer treatment after showing great efficacy in various malignancies. However, its effectiveness in pancreatic ductal adenocarcinoma (PDAC), especially in resectable pancreatic cancer, has not been studied. The primary objective of this study is to compare the OS impact of immunotherapy between PDAC patients who receive neoadjuvant immunotherapy and patients who receive adjuvant immunotherapy. The secondary objective is to investigate the impact of neoadjuvant and adjuvant immunotherapy in combination with chemotherapy and chemoradiation by performing subset analyses of these two groups.MethodsPatients diagnosed with PDAC between 2004 and 2016 were identified from the National Cancer Database (NCDB). Multivariable Cox proportional hazard analysis was performed to examine the effect of neoadjuvant and adjuvant immunotherapy in combination with chemotherapy and chemoradiation on the OS of the patients. The multivariable analysis was adjusted for essential factors such as the age at diagnosis, sex, race, education, income, place of living insurance status, hospital type, comorbidity score, and year of diagnosis.ResultsOverall, 526 patients received immunotherapy. Among whom, 408/526 (77.57%) received neoadjuvant immunotherapy, and the remaining 118/526 (22.43%) received adjuvant immunotherapy. There was no significant difference in OS between neoadjuvant and adjuvant immunotherapy (HR: 1.06, CI: 0.79–1.41; p < 0.714) in the multivariable analysis. In the univariate neoadjuvant treatment subset analysis, immunotherapy was associated with significantly improved OS compared to no immunotherapy (HR: 0.88, CI: 0.78–0.98; p < 0.026). This benefit disappeared in the multivariable analysis. However, after patients were stratified by educational level, the multivariable Cox regression analysis revealed that neoadjuvant immunotherapy was associated with significantly improved OS (HR: 0.86, CI: 0.74–0.99; p < 0.04) compared to no immunotherapy only in patients with high-level of education, but not in patients with low-level of education.ConclusionIn this study, no difference in the OS between patients who received neoadjuvant immunotherapy and patients who received adjuvant immunotherapy was noticed. Future studies comparing neoadjuvant adjuvant immunotherapy combined with chemotherapy, radiation therapy, and chemoradiation are needed.