Single-agent Immune Checkpoint Blockade Research Articles

PD1 inhibition and GITR agonism in combination with fractionated stereotactic radiotherapy for the treatment of recurrent glioblastoma: A phase 2, multi-arm study.

2004 Background: Despite preclinical evidence that fractionated stereotactic radiotherapy (FSRT) is immunostimulatory, there remains a paucity of data regarding immune effects of FSRT in patients treated with immune checkpoint blockade (ICB). To evaluate the immune impact of FSRT in glioblastoma (GBM), which is refractory to single-agent ICB, and to evaluate the efficacy of the addition of FSRT to ICB for this disease, we conducted a phase 2 trial of the combination of retifanlimab (anti-PD1), INCAGN01876 (GITR agonist), and FSRT (8 Gy x 3 fractions) in patients with recurrent GBM (rGBM). Methods: This single-center trial enrolled patients with no prior bevacizumab and dexamethasone dose ≤ 2mg/day. The study included a single-arm, primary efficacy cohort (Cohort A) treated with retifanlimab, INCAGN01876, and FSRT, and a two-arm neoadjuvant window-of-opportunity cohort (Cohort B) for patients needing tumor resection. In Cohort B, patients on Arm B1 received single doses of retifanlimab/INCAGN01876 plus FSRT prior to surgical resection, and patients on Arm B2 received single doses of retifanlimab/INCAGN01876 without FSRT prior to surgical resection. We used flow cytometry on tumor tissue and peripheral blood mononuclear cells and plasma proteomics to explore the immune consequences of neoadjuvant ICB, with vs. without neoadjuvant FSRT. Primary endpoint: ORR in Cohort A (null hypothesis, ORR 5%; alternative hypothesis, ORR 25%; n = 16 for 80% power, α = 0.05). Secondary endpoints: progression-free survival (PFS) and overall survival (OS), separately in Cohorts A, B1, B2. Data cut-off: January 18, 2023. Results: 32 evaluable patients: Cohort A, n = 16; Cohort B, n = 16 (Arm B1, n = 8; Arm B2, n = 8). Median follow-up time: 20 months. Most common grade 3/4 treatment-related adverse events: cerebral edema (34%), fatigue (16%). Efficacy in Cohort A: no objective responses, best response of stable disease in 9/16 patients (56%), median PFS 3.9 months (95% CI 2.1 – 6.2 months), median OS 9.4 months (95% CI 8.2 – 10.6 months). Median PFS and OS were significantly longer in Cohort B1 (neoadjuvant immunotherapy + FSRT) vs. Cohort B2 (neoadjuvant immunotherapy, no FSRT): PFS 11.7 vs. 2.0 months (p = 0.0002), OS 20.1 vs. 9.4 months (p = 0.001). Inflammatory cytokine responses were stronger and more sustained in Cohort B1 vs. Cohort B2, with concomitant increases in proliferative T cell responses. Conclusions: The combination of retifanlimab, INCAGN01876, and FSRT did not demonstrate efficacy in patients with rGBM when administered without surgical resection. However, among patients receiving neoadjuvant immunotherapy prior to surgical resection, the addition of neoadjuvant FSRT was associated with a significant survival advantage as well as increased inflammatory and cellular immune responses. Neoadjuvant FSRT + ICB warrants further evaluation in rGBM. Clinical trial information: NCT04225039 .

Increased co-expression of TIM-3 with TIGIT or 2B4 on CD8+ T cells is associated with poor prognosis in locally advanced nasopharyngeal carcinoma.

The use of immune checkpoint inhibitors in malignant tumors improves patient outcomes. Because single-agent immune checkpoint blockade has a low objective response rate, it is meaningful to explore combined blockade of immune checkpoint receptors. We aimed to investigate the co-expression of TIM-3 with TIGIT or 2B4 on peripheral blood CD8+ T cells from patients with locally advanced nasopharyngeal carcinoma. The correlation between co-expression level and clinical characteristics and prognosis was studied to provide a basis for immunotherapy for nasopharyngeal carcinoma. Flow cytometry was used to detect TIM-3/TIGIT and TIM-3/2B4 co-expression on CD8+ T cells. The differences in co-expression between patients and healthy controls were analyzed. The correlation between co-expression of TIM-3/TIGIT or TIM-3/2B4 and the patient clinical characteristics and prognosis was examined. Also, the correlation between the TIM-3/TIGIT or 2B4 co-expression and other common inhibitory receptors was analyzed. We further validated our results using mRNA data from the Gene Expression Omnibus (GEO) database. TIM-3/TIGIT and TIM-3/2B4 co-expression was upregulated on peripheral blood CD8+ T cells from patients with nasopharyngeal carcinoma. They were both correlated with poor prognosis. There was a correlation between TIM-3/TIGIT co-expression and patient age and pathological stage, whereas TIM-3/2B4 co-expression correlated with age and sex. CD8+ T cells with elevated mRNA levels of TIM3/TIGIT and TIM3/2B4 also showed increased expression of multiple inhibitory receptors, indicating T cell exhaustion in locally advanced nasopharyngeal carcinoma. TIM-3/TIGIT or TIM-3/2B4 can be used as potential targets for combination immunotherapy in locally advanced nasopharyngeal carcinoma.

Abstract 4231: Hypoxia reduction in tandem with anti-angiogenic therapy remodels the pancreatic tumor microenvironment

Abstract Pancreatic cancer patients remain largely unresponsive to single agent immune checkpoint blockade (ICB) therapy. This refractory state originates from PDAC’s unique immunosuppressive microenvironment that is densely populated by suppressive myeloid cells, exhibits poor vascularity, and is highly hypoxic. We previously showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) reduces intratumoral hypoxia through a tissue remodeling process, initiates tumor vasculature reorganization, and sensitizes aggressive, spontaneous murine models of prostate cancer to ICB. In a clinical trial testing the combination of Evofosfamide with cytotoxic T-lymphocyte-associated protein (CTLA-4) blockade (NCT03098160) a subset of metastatic, immune checkpoint blockade refractory patients showed prolonged progression free survival. While these studies highlight hypoxia reduction as therapeutically tractable, we lack complete understanding of the contribution of the tumor vasculature to hypoxia reduction therapy, as well as the downstream consequences of hypoxia reduction on the cellular composition of the tumor microenvironment and the responsiveness to immunotherapy. We used a transplantable, orthotopic pancreatic tumor model derived from Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre mice and a syngeneic prostate tumor model to study tumor responses to hypoxia-reduction, anti-angiogenic therapy, and combination immunotherapy. We find that Evofosfamide with anti-VEGFR-2 (DC101) significantly extends mouse survival. Combination therapy reduces intratumoral hypoxia, improves vessel integrity, and increases intratumoral DNA damage. In response to the improved metabolic microenvironment, CD8 T cells gain enhanced effector function and lose expression of exhaustion-associated features. Like other anti-angiogenic regimens, combination Evofosfamide and DC101 leads to an increased frequency of PD-L1 expressing cells within the tumor, however blockade of PD-1 failed to prolong survival. Bulk-tumor RNA sequencing and tumor infiltrating lymphocyte analysis implicates immature myeloid cells as mediators of resistance. Re-education of the infiltrating myeloid stroma with CD40 agonist could improve responses to hypoxia-reducing, anti-angiogenic therapy. Put together, these data indicate that targeted hypoxic reduction with anti-angiogenic therapy remodels the pancreatic tumor microenvironment. In this setting, CD40 agonist over PD-1 blockade provides an additive benefit in prolonging mouse survival. Citation Format: Arthur J. Liu, Michael A. Curran. Hypoxia reduction in tandem with anti-angiogenic therapy remodels the pancreatic tumor microenvironment [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 4231.

Abstract 1240: Peripherally measured T cell self-renewal capacity associates with response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC)

Abstract Recent studies have suggested that ICB does not primarily restore function to terminally exhausted T cells, but instead drives proliferation and differentiation of progenitor T cells into fresh effector cells. T cell factor 1 (TCF1) marks and maintains T cell self-renewal while repressing differentiation and has been associated with increased antitumor activity. These findings suggest ICB may depend on the continued availability of self-renewing TCF1+ progenitor T cells as the source of fresh effector cells. We hypothesized that characterizing the immunophenotype of T cells in the peripheral blood, with a focus on markers of self-renewal, might be predictive of ICB response. Utilizing an institution-wide biospecimen repository, we evaluated peripheral blood samples using multi-parametric flow cytometry from patients with metastatic NSCLC treated with single-agent ICB who experienced durable clinical benefit (DCB; >1 year of treatment and/or clinical response >1 year) or primary resistance (RES; <6 months of treatment with evidence of disease progression). Our analysis focused on a CCR7- T cell subset, which is characterized by lower proportions of TCF1+ cells but increase during active immune responses. We analyzed samples collected from a cohort of 22 patients, 11 of whom had DCB and 11 with RES. In the pre-treatment samples (n=22), we determined that the frequency of TCF1+CCR7- CD8+ T cells was significantly higher in patients with DCB compared to patients with RES (32.6% v. 19.0%; P = 0.0452). Importantly, the median progression free survival was 17.0 months in patients with TCF1+ frequency above the median compared to 3.0 months in patients with TCF1+ frequency below the median (HR 0.43; P = 0.0185). Among the on-treatment samples (n=19), there was an increased frequency of PD1+ expression within the CCR7- CD8+ T cell subset compared to the paired baseline samples. Examination of those therapy-expanded PD1+ T cells revealed differences in the composition of TCF1+ versus TCF1- fractions in relation to treatment outcome. The mean ratio of TCF1+ to TCF1- amongst PD1+CCR7- T cells on-treatment was found to be significantly higher in the DCB group (1.483 [DCB] v. 0.4791 [RES], P=<0.0001). In this analysis, we identified a pattern of pre-and on-treatment T cell populations that correlates with durable benefit from ICB in patients with NSCLC. We observed that the frequency of TCF1 expression in the more differentiated effector memory T cell subsets prior to treatment correlates with DCB. While on treatment, both groups experienced expansion of PD1+ CD8 T cells, but the presence of greater fractions of TCF1+ T cells in the PD1+ CD8 T cell population correlates with DCB. This finding suggests that persistence and mobilization of self-renewing progenitor T cells is associated with long-lived ICB-induced anti-tumor activity. Citation Format: Rohan Maniar, Peter H. Wang, Robert S. Washburn, Naiyer A. Rizvi, Steven L. Reiner, Brian S. Henick. Peripherally measured T cell self-renewal capacity associates with response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) [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 1240.

Saving TIME: Accuracy of a text intervention to minimize the time burden of cancer care.

6527 Background: Patients with cancer spend substantial time receiving cancer care. There is a need for innovative strategies to decrease the time burden of cancer therapy. The current care model consists largely of in-person visits to assess treatment toxicity. Most patients treated with immunotherapy, however, do not experience substantial toxicity. We designed and evaluated a text-based instrument to identify patients without symptoms of immunotherapy toxicity. This instrument has the potential to be combined with lab assessment to identify individuals who can safely proceed directly to treatment, lessening the need for in-person office visits. Methods: This cross-sectional study evaluated the performance characteristics of a text-based instrument to identify patient-reported immunotherapy toxicity, against the gold standard in-person provider assessment documented in the electronic medical record (EMR). Those eligible for inclusion spoke English, were receiving single agent immune checkpoint blockade for a solid tumor, and had access to a mobile device with text messaging capabilities. The instrument contained 16 questions adapted from the NCI Pro-CTCAE and was administered via text-message 96 hours prior to the patient’s scheduled infusion visit. Patient perspectives were quantified via a 13-item questionnaire. Results: Between October 1 and November 25, 2021, 50 patients enrolled in the study, and 45 patients completed the instrument (90% response). The median age was 68 (IQR 60-72), 31 (62%) were male, and 44 (88%) were white. Most patients received either pembrolizumab (n=27, 54%) or nivolumab (n=17, 34%) in the palliative setting (n=37, 74%) for genitourinary (n=15, 30%), lung (n=13, 26%), or skin (n=11, 22%) cancer. Patients who completed the instrument were younger (median age 67 vs 76) than those who did not complete the instrument. The prevalence of immune related toxicity documented in the EMR was 57.8%. The sensitivity and negative predictive value of the instrument was 100% (95% CI 0.87-1.00) and 100% (95% CI 0.664-1.00), respectively; other accuracy parameters are presented in the Table. The patient user questionnaire revealed that visual impairment, lack of access to a smart phone, and lack of recognition of the instrument were barriers to completion. Conclusions: A text-based platform is both feasible and effective at identifying patients who are not experiencing symptoms of immune toxicity, and when combined with lab assessment, can eliminate office visits for up to 47% of patients. A prospective clinical trial to assess this is underway (NCT05134636). [Table: see text]

Revolumab: A phase II trial of nivolumab in recurrent IDH-mutant high-grade gliomas.

2048 Background: Novel effective treatments are urgently needed for IDH-mutant high-grade gliomas (HGGs) recurring after radiotherapy and chemotherapy. While single-agent immune checkpoint blockade (ICB) showed limited efficacy in IDH-wildtype glioblastoma, results in IDH-mutated HGGs are not yet available. In this multicenter, single-arm, phase II trial (REVOLUMAB, NCT03925246), we assessed the efficacy of the anti-PD1 Nivolumab in recurrent IDH-mutant HGGs. Methods: Main eligibility criteria: adult patients with IDH-mutant HGG recurring after radiotherapy and ≥ one line of alkylating chemotherapy, KPS > 50%, less than 10mg/day prednisone equivalent. The primary endpoint was the 24-weeks progression-free survival (PFS) rate according to the RANO criteria by investigator assessment. Patients received intravenous Nivolumab 240 mg every 2 weeks for 8 cycles, followed by 480 mg every 4 weeks for a maximum duration of one year. 39 patients were planned to be enrolled based on a one-stage A’Hern’s design (p0 = 30%, p1 = 50%, type I error rate = 5%, power = 80%). Results: Between July 2019 and June 2020, 39 patients with recurrent IDH-mutant HGG (n = 21 WHO grade 3, 13 grade 4, and 5 grade 2 tumors with MRI evidence of anaplastic transformation; n = 10 1p/19q- codeleted, 17 non-codeleted tumors) were enrolled. The median follow-up duration was 17.6 months (11.6-24). The median time since diagnosis was 4.05 years (0.39-16.72), the median time since radiotherapy was 4.47 years (0.55-12.66), the median number of previous chemotherapy lines was 2 (1-4). Eight patients completed Nivolumab treatment as planned, thirty patients stopped treatment due to tumor progression and one patient due to adverse event (AE) unrelated to study drug. At 24 weeks, 11/39 patients were alive without disease progression (28.2% CI95% [15%; 44.9%]). According to RANO, one patient (2.6%) achieved complete response (CR), 3 patients (7.7%) partial response (PR), 13 patients (33.3%) stable disease, and 22 (56.4%) had progression as their best response. Median PFS and OS were 1.84 (CI95% [1.81 ; 5.89]) and 14.7 months (CI95% [9.18; NR]), respectively. There was no difference in PFS between 1p/19q-codeleted and non-codeleted tumors. No patient definitively stopped Nivolumab due to side effects; the safety profile was consistent with prior studies of Nivolumab in gliomas and other cancers. Conclusions: To our knowledge, this is the first reported trial of ICB in IDH-mutant gliomas. Nivolumab failed to achieve its primary endpoint. However, Nivolumab was well tolerated and long-lasting responses were observed in a subset of this population, which support further evaluation in combination with other agents such as anti-VEGF or IDH inhibitors. This trial was funded by French Ministry of Health.The sponsor was Assistance Publique – Hôpitaux de Paris. Study drug was supplied by Bristol Myers Squibb (CA209-818). Clinical trial information: NCT03925246.

Randomized phase II trial of durvalumab (anti-PDL1) and tremelimumab (anti-CTLA4) administered in combination versus sequentially for the treatment of recurrent platinum-resistant non-clear cell ovarian cancer (NCT03026062)

<h3>Objectives:</h3> Single agent immune checkpoint blockade (ICB) has demonstrated response rates of 5-15% in patients with recurrent high-grade ovarian cancer (HGOC), with another 15-40% of patients achieving stable disease. Combination ICB using ipilimumab and nivolumab resulted in improved response rates in a mixed population with platinum resistant and sensitive disease. The objective of the current trial was to evaluate sequential versus combination CTLA4 and PDL1 blockade strategies for extending progression free survival (PFS) in patients with platinum resistant/refractory HGOC. <h3>Methods:</h3> Patients were required to have pathologically confirmed platinum resistant or refractory epithelial ovarian cancer, no prior immunotherapy, and PS=0-1 for enrollment. The current abstract includes data only on subjects with high grade serous ovarian cancer (HGSOC), as enrollment of patients with clear cell histology is still ongoing. The primary endpoint was PFS and response was assessed using modified RECIST v1.1. Unlimited numbers of prior regimens were allowed. Patients were adaptively randomized to sequential arm: tremelimumab (3mg/kg q4 weeks x 4 doses) followed by durvalumab (1.5g IV q4 weeks for up to 9 doses) upon progression, or the combination arm: tremelimumab (1mg/kg IV plus durvalumab 1.5g IV q4wk for up to 4 doses followed by durvalumab monotherapy for up to 9 doses). For the Bayesian adaptive randomization, the probability of being assigned to an arm was proportional to the likelihood the arm had better PFS, such that patients were more likely to be randomized to the more effective arm. <h3>Results:</h3> A total of 61 subjects were adaptively randomized to sequential treatment (n=38) or combination therapy (n=23). 46 (79%) patients had wild-type breast cancer gene (<i>BRCA</i>). Median prior lines of therapy was 4 (range: 1-10). There was no difference in median PFS in the sequential arm (1.84 months; 95% CI: 1.77 – 2.17)) compared with the combination arm (1.87 months; 95% CI: 1.77 – 2.43), p=0.402. Similarly, median OS in the sequential and combination arms were 10.61 months (5.95 – 15.34) and 7.26 (4.24 – 15.57), respectively (p=0.810). In the sequential arm no objective responses were observed, although 12 patients (31.6%) exhibited stable disease. In the combination arm, 2 patients had partial response (8.7%) while one additional patient (4.4%) had stable disease. The adverse event profile was consistent with that previously reported for immune checkpoint therapy. <h3>Conclusions:</h3> There was no difference in the median PFS between the combination and sequential durvalumab plus tremelimumab treatment strategy arms in a heavily pretreated population of patients with platinum resistant/refractory HGOC. Response rates were comparable to prior reports, though the combination regimen did not add significant benefit as has been previously described with combination of ipilimumab/nivolumab. Further exploration into subpopulations that may have increased benefit from ICB is warranted.

Multidisciplinary Management of Brain Metastases from Non-Small Cell Lung Cancer in the Era of Immunotherapy.

Brain metastases from non-small cell lung cancer often cause neurologic symptoms which lead to initial diagnosis or identification of recurrence. In other patients, they are identified on surveillance imaging or when a patient undergoing treatment develops neurological symptoms. Patients with symptomatic lesions should be started on dexamethasone and evaluated by a neurosurgeon as soon as possible. If feasible, surgery should be offered to decrease intracranial pressure, alleviate symptoms, and prevent irreversible neurological damage. Postoperative stereotactic radiosurgery (SRS) to the resection cavity and any additional brain metastases should follow within 4 weeks of surgery, as early as 2 weeks post-op. Tissue from surgery is used to confirm the diagnosis and test for targetable oncogenic driver mutations. Treatment response and surveillance for development of additional lesions is assessed with MRI of the brain 1 month after SRS and every 3 months thereafter. Patients who are not surgical candidates or who have small, asymptomatic brain metastases should proceed with SRS, the preferred treatment, or sometimes whole-brain radiation therapy (WBRT) if multifocal disease requires more extensive treatment, such as for leptomeningeal spread of disease. The number of brain metastases that warrants use of WBRT over SRS is controversial and a topic of ongoing investigation, and is discussed in this review. When possible, SRS is preferred over WBRT due to reduce morbidity and cognitive side effects. When patients are already on systemic therapy at time of brain metastases diagnosis, systemic therapy should continue, with radiation therapy occurring between cycles. Regarding systemic therapy for new diagnosis at time of brain metastases presentation, molecular testing will guide treatment choice, when available. If there is no neurosurgical intervention, biopsy of another site of disease may provide tissue for molecular testing. If there are no targetable oncogenic driver mutations, concurrent immune checkpoint blockade (ICB) and chemotherapy is preferable for patients who can tolerate it. Single-agent ICB is an alternative option for patients who cannot tolerate chemotherapy. Systemic therapy should start as soon as possible. In some patients with poor performance status, best supportive care may be the most appropriate choice. Treatment decisions should always incorporate patients' goals of care and in many cases should be discussed in a multidisciplinary setting.

Association of homologous recombination deficiency in ovarian cancer with neoantigen load and expression of immune checkpoints.

5536 Background: Immune checkpoint blockade (ICB) is being explored as a treatment option in ovarian cancer, but objective response rates for single agent ICB are modest at around 10-15%. Validated biomarkers are needed to predict which patients will respond to ICB. BRCA mutations and homologous recombination deficiency (HRD) status are the only validated integral biomarkers in ovarian cancer. HRD tumors exhibit defective DNA repair mechanisms that promote increased mutational burden, which we postulate may correlate with higher neoantigen load and increased expression of targetable immune checkpoints. Methods: The Cancer Genome Atlas (TCGA) ovarian cancer dataset was evaluated and previously published, well annotated samples were obtained for HRD status. HLA type was determined with OptiType. Nonsynonymous mutations were annotated with Ensembl VEP. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 amino acids in length for MHC class I, reporting only those with a predicted IC50 less than 500 nM. Immune checkpoint gene expression counts were normalized with TCGAbiolinks. Correlation between HRD status and neoantigen load was assessed by Wilcoxon test. After log2 transformation, Wilcoxon tests evaluated for association between HRD status and expression of immune checkpoints. The relationship between HRD status and PD-L1 protein abundance with reverse phase protein array was measured. Results: Data from 154 HRD positive and 198 HRD negative tumors were analyzed. HRD positive status correlated with higher neoantigen load (p = 0.038) and increased expression of the immune checkpoints CTLA4 (p = 0.024), TIGIT (p = 0.027), and PVR (p = 0.002), but not PD-L1 (p = 0.238), LAG3 (p = 0.583), HVEM (p = 0.805), GAL9 (p = 0.750), NECTIN2 (p = 0.874), VSIG3 (p = 0.438), PSGL1 (p = 0.205) or VISTA (p = 0.531). TIM3 (p = 0.064) and B7H3 (p = 0.052) both demonstrated a trend towards increased expression in HRD tumors. Interestingly, HRD status showed a negative association with PVRIG (p = 0.028). There was no association between PD-L1 protein abundance and HRD status. Conclusions: HRD positive ovarian tumors demonstrate higher neoantigen load than HRD negative tumors, as well as increased expression of certain immune checkpoints. This supports the hypothesis that increased neoantigen load leads to compensatory induction of immune checkpoints, and suggests that HRD status may predict response to ICB, particularly to drugs that target CTLA4, TIGIT, PVR, TIM3 and B7H4.

Druggable epigenetic suppression of interferon-induced chemokine expression linked to MYCN amplification in neuroblastoma

BackgroundAmplification of the MYCN oncogene is a molecular hallmark of aggressive neuroblastoma (NB), a childhood cancer of the sympathetic nervous system. There is evidence that MYCN promotes a non-inflamed and...

Immunotherapy in Advanced Biliary Tract Cancers.

Simple SummaryA new era has emerged in oncology in the last ten years with the development of immune therapies. However, single-agent immune therapy such as immune checkpoint inhibitors seems to have a limited clinical activity in biliary tract cancers and are still largely investigational, except for the few patients with microsatellite-instable tumors. Here, we review: (i) the molecular and immune landscape of biliary tract cancers, (ii) the existing results of immune therapies in biliary tract cancers, and (iii) the future of immune therapies in biliary tract cancers, with the identification of predictive biomarkers for response to these therapies, and the ongoing therapeutic trials.Biliary tract cancers are rare tumors with a poor prognosis. Two-thirds of these primary liver malignancies are diagnosed at advanced stages where therapeutic options are limited. Whereas several molecular targeted therapies emerge in biliary tract cancers, immunotherapy is still investigational, the only approved immunotherapy to date being the immune checkpoint inhibitor pembrolizumab for the small fraction of patients with microsatellite-instable tumors. In microsatellite-stable, pre-treated biliary tract cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients. The identification of predictive biomarkers will allow a better selection of patients that may benefit from immunotherapy. Combinations of immunotherapies with each other, with chemotherapy or targeted molecular therapies are being investigated in early lines of therapy, including first-line.

A pilot trial of neoantigen DNA vaccine in combination with nivolumab/ipilimumab and prostvac in metastatic hormone-sensitive prostate cancer (mHSPC).

TPS192 Background: Despite robust advances in the use of immune checkpoint blockade (ICB) across multiple cancer types, responses in prostate cancer remain suboptimal. Overall response rates for single-agent ICB in prostate cancer are low, but recent modest gains have been made with ipilimumab and nivolumab combination therapy in metastatic castrate-resistant prostate cancer. Prostvac-VF Tricom is a therapeutic vaccine that incorporates DNA for the shared self-antigen PSA into the vaccinia (or fowlpox) virus strain. A large randomized phase III clinical trial recently showed no improvement in overall survival (OS) with Prostvac compared with placebo, suggesting that a combinatorial approach is warranted. Personalized neoantigen vaccines based on specific mutated epitopes may have the ability to overcome immunoresistance seen with self antigens. Even in low mutational burden tumors like prostate cancer, T cell responses against neoantigens are observed in patients with favorable clinical outcomes, supporting neoantigen vaccination as a promising therapeutic strategy. Improvements in computational genomics and predictive algorithms have allowed the incorporation of MHC class II neoepitopes and those from gene fusion events relevant in prostate cancer. We thus hypothesized that a strategy utilizing both shared antigen (Prostvac) and personalized MHC-I and MHC-II neoantigen vaccines combined with dual ICB would induce robust immune responses and improve clinical outcomes. To maximize tumor burden reduction and minimize tumor-mediated immunoresistence, we are evaluating this novel strategy in patients with metastatic hormone-sensitive prostate cancer (mHSPC) who have completed frontline docetaxel chemotherapy. Methods: This ongoing trial (NCT03532217) began accrual in September 2018. Eighteen of 20 planned patients have been enrolled to date. Eligible patients have histologically confirmed high risk/volume mHSPC defined as 4 or more sites of metastatic disease or visceral involvement. Patients receive continuous androgen deprivation therapy (ADT) and have completed upfront docetaxel chemotherapy. Patients begin treatment with Prostvac-VF in combination with ipilimumab (1 mg/kg every 3 weeks for 2 doses), and nivolumab (3 mg/kg every 3 weeks for 6 doses) within 60 days of the last dose of docetaxel. Subsequently, patients receive nivolumab 480 mg IV every 4 weeks in conjunction with a personalized neoantigen DNA vaccine administered monthly via intramuscular electroporation. The primary objective of this exploratory study is to assess the feasibility, safety/tolerability, and immune responses of this combination strategy. Key secondary objectives include failure-free survival and milestone survival at 2 years, PSA response, and radiographic progression-free survival. Clinical trial information: NCT03532217.

Abstract PS17-14: Evaluating the efficacy of immunotherapy in triple negative breast cancer

Abstract The breast cancer microenvironment comprises a complex stroma including tumor-infiltrating lymphocytes (TILs), which can either stimulate tumor progression or promote anti-tumor immunity in response to tumor-derived cues. In general, of all clinical subtypes, triple-negative breast cancer (TNBC) is characterized by the most extensive infiltration of TILs within tumor stroma, which is consistent with the observation that TNBC seems to clinically respond to immunotherapies at the highest rates. Immune checkpoint blockade (ICB), an immunotherapy that promotes prolonged activation of cytotoxic immune cells to mount robust anti-tumorigenic responses, has yielded limited success in treating breast cancer. IMpassion130 was the first clinical trial to indicate that combining anti-PD-L1 with standard-of-care chemotherapy (nab-paclitaxel) to treat TNBC increases progression-free survival in patients exclusively those with PD-L1 positive tumors. Furthermore, the KEYSTONE-522 trial showed that administering anti-PD-1 in addition to various neoadjuvant chemotherapies increased the pathologic complete response in early stage TNBC patients. Despite promising evidence for immunotherapy success, both clinical trials lacked an experimental ICB-only group, and thus cannot address the therapeutic benefit of ICB alone, or which chemotherapy combination would maximize this benefit. Finally, mechanisms of resistance to ICB in breast cancer remain unexplored. We sought to model ICB response in vivo to elucidate the mechanisms responsible for immunotherapy efficacy in breast cancer, explore the synergistic effects of ICB with chemotherapies, and model ICB resistance.In this study, we investigated the efficacy of anti-PD-L1 as single-agent or in combination with paclitaxel or doxorubicin in the EMT6 (Balb/c) orthotopic mammary tumor model. In this model, single-agent immunotherapy was efficacious in reducing primary tumor growth compared to combination treatment, with a small proportion of complete responses, whereas modest benefit was observed with either chemotherapy alone. Following two rounds of treatment, we analyzed the tumor-immune microenvironment by flow cytometry and gene expression analysis. Anti-PD-L1 alone or in combination with either chemotherapy enhanced infiltration of cytotoxic and effector T cell as well as natural killer cells into the tumor microenvironment. Using gene expression analysis, we observed elevated expression of myeloid recruitment and activation markers in combination-treated tumors, supporting a known role of chemotherapy-induced cell death in myeloid recruitment; however as chemotherapy did not add benefit to tumor response or survival, it is unclear if this effect is detrimental or supportive. Interestingly, completely responsive anti-PD-L1 treated tumors that eventually recurred retained resistance to ICB upon re-implantation in naïve recipient mice, suggesting that tumor-intrinsic factors may contribute to resistance.Herein, we explore an in vivo model that corroborates clinical response to combinatorial immunotherapy approaches in breast cancer patients. We report the immunogenic efficacy of single-agent ICB that upregulates tumoricidal immune cell infiltration into the primary tumor, thereby controlling tumor growth, albeit without achieving complete response in all mice. Additionally, post-therapy recurrent tumors retain resistance upon transplantation, indicating tumor-specific adaptive resistance. This study has potentially significant clinical implications for re-evaluating the contributions of chemotherapy in combination with ICB in TNBC patients. Citation Format: Ann Hanna, Paula I. Gonzalez-Ericsson, Violeta Sanchez, Melinda E. Sanders, Justin M. Balko. Evaluating the efficacy of immunotherapy in triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-14.

Immune checkpoint inhibitors in driver mutation-positive nonsmall cell lung cancer: is there a role?

Despite advances in immunotherapy for nonsmall cell lung cancer patients, the clinical efficacy of drugs for patients with oncogenic driver mutations remains limited. This article aimed to comprehensively review the currently available data on the efficacy and safety of immune checkpoint blockade (ICB) for patients with driver mutation-positive lung cancer. Despite the positive interaction between activation of oncogenic pathways and upregulated PD-L1 expression demonstrated in preclinical studies, the efficacy of single-agent ICB in patients with oncogenic mutation has largely been discouraging, except for those with KRAS mutations. The combination therapies using ICB with tyrosine kinase inhibitors (TKIs) for EGFR/ALK alteration raised a concern for the high incidence of treatment-related adverse events, notably hepatotoxicity and interstitial lung disease. A novel combination with bevacizumab demonstrated promising efficacy with tolerable safety profiles. Other than patients with the KRAS mutation who demonstrate relatively favorable response to ICB, a single-agent ICB therapy should be considered for those who retain good performance status but have no other therapeutic options available. Further studies on the combination of ICB and TKI are needed to identify the most viable pair regarding safety. Additional studies using novel combination partners, such as anti-VEGF inhibitors, are also warranted.

Efficacy and safety of immune checkpoint blockade in self-identified Black patients with advanced non-small cell lung cancer.

To the authors' knowledge, race-based differences in efficacy for the treatment of patients with advanced non-small cell lung cancer (NSCLC) have not been studied to date due to the underrepresentation of patients of minority backgrounds in pivotal trials. In the current study, the authors examined real-world differences in outcome in a diverse patient population. The authors retrospectively analyzed the clinical outcomes of patients with advanced NSCLC who were treated with single-agent immune checkpoint blockade (ICB) between 2013 and July 2018 at Winship Cancer Institute of Emory University in Atlanta, Georgia. Primary efficacy comparison between Black patients and White patients was performed using bivariate and multivariate analyses for overall survival (OS) and progression-free survival (PFS). Data from 257 patients were analyzed. The median age of the patients was 69years; 50.6% of the patients were female, 63.4% were White, 29.5% were Black, and 7.1% of the patients were of "other" race. ICB was the first-line treatment in 51 patients (19.9%), the second-line treatment in 161 patients (62.6%), and the third-line treatment in 33 patients (12.9%). The most commonly used agents were nivolumab (49.0%), pembrolizumab (25.2%), and atezolizumab (21.3%). No differences with regard to OS (P=.839) and PFS (P=.235) were noted between Black and White patients. The sample overall response rate was 20.6% (15.2% in Black patients and 23.1% in White patients). No differences with regard to OS (P=.081) and PFS (P=.176) were observed between female and male patients. The rate of immune-related adverse events was found to be similar in Black and White patients (20.0% vs 29.9%; P=.148). On multivariate analysis, race was not found to be significantly associated with OS or PFS. Real-world analysis of the authors' institutional experience demonstrated similar efficacy and tolerability of ICB in Black versus White patients with advanced NSCLC. Larger multi-institutional studies including other US minority populations would make the findings of the current study more generalizable.

Immunotherapy for advanced thyroid cancers - rationale, current advances and future strategies.

In the past decade, the field of cancer immunotherapy has been revolutionized by immune checkpoint blockade (ICB) technologies. Success across a broad spectrum of cancers has led to a paradigm shift in therapy for patients with advanced cancer. Early data are now accumulating in progressive thyroid cancers treated with single-agent ICB therapies and combination approaches that incorporate ICB technologies. This Review discusses our current knowledge of the immune response in thyroid cancers, the latest and ongoing immune-based approaches, and the future of immunotherapies in thyroid cancer. Physiologically relevant preclinical mouse models and human correlative research studies will inform development of the next stage of immune-based therapies for patients with advanced thyroid cancer.

Abstract IA19: Immunotherapy in ovarian cancer: Challenges and novel opportunities

Abstract IA19: Immunotherapy in ovarian cancer: Challenges and novel opportunities

Immunotherapy in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancers. The prognosis remains poor—the 5‑year overall-survival (OS) is 12–18%, all stages taken together. Systemic therapy has been limited to the use of tyrosine kinase inhibitors for more than a decade. Now immune therapy has also arrived in the field of systemic HCC treatment. Despite initial enthusiasm, the response rate to single agent immune checkpoint blockade (ICB) in HCC patients is approximately 15–20%. The immune tolerance of the liver and cirrhosis-associated immune dysfunction (CAID) may play a role in the immunological tumor escape phenomenon. The two phase 3 trials of pembrolizumab vs. placebo in second-line treatment (KEYNOTE-240) and nivolumab vs. sorafenib in first-line treatment (CheckMate 459) did not reach their primary endpoint of OS benefit. Pleasant news from IMbrave150 were recently published: the combination therapy of atezolizumab and bevacizumab reached significant benefit in overall response rate (ORR) and overall survival (OS) compared to current standard of care (SOC) sorafenib in patients advanced HCC in first-line therapy.

Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2−negative endocrine-refractory metastatic breast cancer

BackgroundResponse rates to single agent immune checkpoint blockade in unselected pretreated HER2−negative metastatic breast cancer (MBC) are low. However, they may be augmented when combined with chemotherapy.MethodsWe conducted a single-arm,...

Abstract AP22: DNA DAMAGE RESPONSES AND IMMUNE PROFILING THROUGH HIGHLY MULTIPLEXED TISSUE IMMUNOFLUORESCENCE (T-CYCIF) IN HIGH-GRADE SEROUS OVARIAN CANCER

Abstract INTRODUCTION: Immune checkpoint blockade (ICB) has emerged as a new therapeutic approach for multiple cancers, however, the responses to single-agent ICBs have been modest in high-grade serous ovarian cancer (HGSOC). Preclinical and early clinical data indicate promising efficacy of combination with DNA damaging agents and immunotherapy, however lack of functional- and tissue geographical knowledge on the interplay between DNA repair and immune activation has hampered the future development of these strategies. The majority of HGSOC are deficient in homologous recombination (HR) DNA repair, and this deficiency is associated with increased immune recognition and potentially increased response to ICBs. Compelling evidence has shown that DNA damaging agents increase the expression of immune-regulatory genes, such as interferons, which can potentially overcome resistance to ICB. There is a critical need for a deeper understanding of the dynamics between DNA damage in cancer cells and anti-tumor immune responses in HGSOC in order to find rational combinations and predictive biomarkers for DNA damaging agents and immunotherapy. RESULTS: We are employing a novel, high-multiplex tissue cyclic immunofluorescence (t-CycIF) platform allowing for the simultaneous detection of up to 60 different antigens at single cell resolution. To reveal the effects of between intrinsic and treatment-induced DNA damage in HGSOC, we are profiling the microenvironments in HGSOCs with inherent DNA repair deficiencies, and after DNA damaging therapy. We collected clinically annotated cohorts of 37 BRCA1/2 mutated and 17 HR wild-type patients (Strickland et al, 2016), as well as six paired pre- and post-treatment and 18 post-treatment tumor samples from patients undergoing neoadjuvant chemotherapy (NACT). Using image analysis we generated highly multiplexed single cell data for over 106 cells. Through supervised clustering, we evidenced distinct cell compositions in the tumor microenvironment of BRCA1/2 mutated and HR-wild type HGSOCs. Consistent with the role of immune-suppression in HGSOC progression, we found that high infiltration of CD4/FOXP3+ regulatory T-cells associated with more actively proliferating cancer cells. Interestingly, tumors with high expression of PD1/PD-L1 were found to have high infiltration of CD1c+ dendritic cells potentially indicating active suppression of antigen presenting pathways in these tumors. Further, tumors with high levels of DNA damage show active interferon signaling, which associated with significantly higher CD8+ cytotoxic T-cell infiltration. In addition, our preliminary evidence suggests heterogenous DNA damage response- and immune profiles in samples collected after NACT. CONCLUSIONS: BRCA1/2 mutated tumors have a distinct microenvironment compared to HR-wt HGSOC. In support of earlier findings, FOXP3+ T-cells contribute to immune suppression in HGSOC. The high infiltration of dendritic cells and PD1/PD-L1 expression indicates a subgroup of HGSOC that are likely sensitive to ICBs. Further, increased DNA damage and interferon pathway activation delineated a more immunogenic subset of HGSOC. We conclude that t-CycIF could accelerate the development of rational strategies for combining DNA damaging agents with immunotherapy to ultimately improve the treatment and outcomes of patients with ovarian cancer. Citation Format: Anniina Färkkilä, Jia-Ren Lin, Zoltan Maliga, Sameer S. Chopra, Bose Koruchupakkal, Brooke E. Howitt, Kyle C. Strickland, Sandro Santagata, Elizabeth M. Swisher, Ursula A. Matulonis, Jennifer. L. Guerriero, Kevin Elias, Panagiotis Konstantinopoulos, Peter K. Sorger, and Alan D. D'Andrea. DNA DAMAGE RESPONSES AND IMMUNE PROFILING THROUGH HIGHLY MULTIPLEXED TISSUE IMMUNOFLUORESCENCE (T-CYCIF) IN HIGH-GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP22.