anti-PD1 Checkpoint Inhibitor Research Articles

Immune checkpoint inhibitors in combination with radiotherapy as salvage treatment for relapsed/refractory classical Hodgkin lymphoma: A retrospective analysis in 12 patients.

The rate of complete remission (CR) with the anti-PD1 immune checkpoint inhibitors (ICI) nivolumab (N) and pembrolizumab (P) in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) is low (20-30%), and the majority of patients eventually relapse. One strategy to improve their outcome is to combine ICI with radiotherapy (ICI-RT), taking advantage of a supposed synergistic effect. We retrospectively collected data of 12 adult patients with R/R cHL treated with ICI-RT delivered during or within 8 weeks from the start or after the end of ICI. Median age at ICI-RT was 37 years, 50% had previously received an autologous stem cell transplantation (SCT) and 92% brentuximab vedotin. RT was given concurrently, before or after ICI in 4, 1 and 7 patients. Median RT dose was 30Gy, for a median duration of 22 days. Median number of ICI administrations was 15. Overall response and CR rate were 100% and 58%. Nine patients received subsequent SCT consolidation (7 allogeneic and 2 autologous). After a median follow-up of 18 months, 92% of patients were in CR. No major concerns about safety were reported. ICI-RT combination appears to be a feasible and highly active bridge treatment to transplant consolidation.

Impact of ECOG performance status on recurrent/metastatic head and neck squamous cell carcinomas treated with anti-PD1 inhibitors.

e18004 Background: Anti-PD1 checkpoint inhibitors (ICI) represent an established standard of care for patients with recurrent/metastatic head & neck squamous cell carcinoma (RMHNSCC). Landmark studies excluded patients with ECOG performance status (PS) ≥ 2; the benefit of ICI in this population is therefore unknown. Methods: We retrospectively reviewed RMHNSCC patients who received at least 1 dose of ICI at our institution. Demographic data and clinical outcomes were obtained; the latter included objective response to ICI (ORR), physician-documented CTCAE grade 2+ toxicity (irAE), and any unplanned hospitalization within 100-days of last ICI dose (UH). Associations between demographic data and clinical outcomes were explored using both uni- and multivariate analysis. Overall survival (OS) was estimated using a Cox proportional hazards model; ORR, irAE, and UH were evaluated with logistic regression. This project was approved by our institutional IRB. Results: We identified 152 RMHNSCC patients who were treated with ICI between 1/2013 and 1/2019. ECOG PS was 0 in 42 (27%), 1 in 75 (50%), 2 in 27 (18%), 3 in 2 (1%), and unknown in 6 (4%) patients. The median age was 61 (range: 25 - 90). 124 (82%) were male, 124 (82%) were white, and 69 (45%) were never-smokers. The most common primary sites were the oropharynx (n = 59, 40%), oral cavity (n = 39, 26%), nasopharynx (n = 11, 7%), and larynx (n = 10, 6%). 54 (36%) were p16+ oropharynx cancers. CPS score was available in 10 (6.6%). Single agent ICI was received by 118 (77%) patients. 66 (44%) had a documented irAE and 54 (36%) had an UH. A multivariate model for OS containing PS, smoking status and HPV status showed a strong association between inferior OS and ECOG 2/3 compared to 0/1 (p < 0.001; HR = 3.30, CI = 2.01-5.41), as well as former (vs. never) smoking status (p < 0.001; HR = 2.17, CI = 1.41-3.35). Current smoking (p = 0.25) did not reach statistical significance. On univariate analysis, poor PS was associated with inferior ORR (p = 0.03; OR = 0.25, CI = 0.06-0.77) and increased UH (p = 0.04; OR = 2.43, CI = 1.05—5.71). There was no significant association between irAE and any patient characteristic. Conclusions: We observed inferior overall survival among ICI-treated RMHNSCC patients with ECOG 2/3 in our single-institution, retrospective series. Our findings help frame discussion of therapeutic options in this poor-risk population. Further study must be done to determine which interventions are of greatest benefit for RMHNSCC patients with declining performance status.

MDNA11 is a long-acting IL-2 superkine that potentiates durable immune response in mouse tumor models and non-human primates.

e14546 Background: The efficacy and safety of recombinant human IL-2 (rhIL-2; Proleukin) to treat certain cancers is limited by a short half-life, marked toxicity and selective high affinity binding to IL2Ra over IL2Rb, resulting in preferential activation of suppressive Tregs. In contrast, MDNA11 has been engineered as a long-acting IL-2 superkine with high affinity IL2Rb receptor selectivity, resulting in preferential anti-cancer effector immune cell activation. Methods: MDNA11 was characterized in both in vitro and in vivo studies including assessment of receptor binding kinetics using BLI/Octet, receptor-mediated signaling in human PMBCs, efficacy in syngeneic mouse tumor models including memory response, as well as safety and PK/PD assessments in non-human primates (NHP). Results: Unlike rhIL-2, MDNA11 does not bind to human IL2Ra but demonstrates a 30-fold higher affinity binding to human IL2Rb. This selectivity resulted in enhanced in vitro STAT5 signaling in human NK and resting CD8 T cells with diminished signaling in Tregs; validation studies in humanized mice are ongoing. In CT26 and MC38 syngeneic tumor models, MDNA11 demonstrates potent and durable efficacy as monotherapy following a Q1W dose schedule for 2 weeks. Synergy with anti-PD1 and anti-CTLA4 immune checkpoint inhibitors (ICIs) was observed and a robust immune memory response developed in all mice with complete tumor clearance. These mice were protected against relapse and tumor re-challenges for up to 8 months without any further treatment, and showed the presence of antigen-specific CD8 T cells. In binding studies with IL-2 receptors of different species, MDNA11 showed highly similar affinity towards human and cynomolgus IL2Rb, confirming the latter as a highly relevant model for toxicology study. MDNA11 was well tolerated in cynomolgus monkeys up to 0.6 mg/kg, while inducing durable (≥10 days) proliferation and expansion of NK and CD8 T cells. Effects on Tregs were minimal and there was no eosinophilia and hypotension (associated with vascular leak syndrome). At high doses of MDNA11, the most common clinical observations were transient loss of appetite and diarrhea. There was modest increase in levels of IFNg and TNFa, but no sign of cytokine release syndrome. Dosing did not trigger development of anti-drug antibodies or histopathologic evidence of pulmonary edema (a major IL-2 induced toxicity). Conclusions: MDNA11 is a long-acting IL-2 superkine that exhibits robust efficacy in mouse tumor models as a single agent and was synergistic in combination with ICIs (anti-CTLA4 and anti-PD1). In NHP, MDNA11 demonstrates selective immune effector cell activation and a favorable safety profile. These data constitute a strong framework for the design of a pivotal GLP toxicology study to further support the planned clinical study of MDNA11 either as a single agent or in combination with ICIs.

Single-cell characterization of macrophages in glioblastoma reveals MARCO as a mesenchymal pro-tumor marker

BackgroundMacrophages are the most common infiltrating immune cells in gliomas and play a wide variety of pro-tumor and anti-tumor roles. However, the different subpopulations of macrophages and their effects on the tumor microenvironment remain poorly understood.MethodsWe combined new and previously published single-cell RNA-seq data from 98,015 single cells from a total of 66 gliomas to profile 19,331 individual macrophages.ResultsUnsupervised clustering revealed a pro-tumor subpopulation of bone marrow-derived macrophages characterized by the scavenger receptor MARCO, which is almost exclusively found in IDH1-wild-type glioblastomas. Previous studies have implicated MARCO as an unfavorable marker in melanoma and non-small cell lung cancer; here, we find that bulk MARCO expression is associated with worse prognosis and mesenchymal subtype. Furthermore, MARCO expression is significantly altered over the course of treatment with anti-PD1 checkpoint inhibitors in a response-dependent manner, which we validate with immunofluorescence imaging.ConclusionsThese findings illustrate a novel macrophage subpopulation that drives tumor progression in glioblastomas and suggest potential therapeutic targets to prevent their recruitment.

Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches

Anticytotoxic T lymphocyte-associated protein 4 (CTLA4) antibodies have shown potent antitumor activity, but systemic immune activation leads to severe immune-related adverse events, limiting clinical usage. We developed novel, conditionally active biologic (CAB) anti-CTLA4 antibodies that are active only in the acidic tumor microenvironment. In healthy tissue, this binding is reversibly inhibited by a novel mechanism using physiological chemicals as protein-associated chemical switches (PaCS). No enzymes or potentially immunogenic covalent modifications to the antibody are required for activation in the tumor. The novel anti-CTLA4 antibodies show similar efficacy in animal models compared to an analog of a marketed anti-CTLA4 biologic, but have markedly reduced toxicity in nonhuman primates (in combination with an anti-PD1 checkpoint inhibitor), indicating a widened therapeutic index (TI). The PaCS encompass mechanisms that are applicable to a wide array of antibody formats (e.g., ADC, bispecifics) and antigens. Examples shown here include antibodies to EpCAM, Her2, Nectin4, CD73, and CD3. Existing antibodies can be engineered readily to be made sensitive to PaCS, and the inhibitory activity can be optimized for each antigen's varying expression level and tissue distribution. PaCS can modulate diverse physiological molecular interactions and are applicable to various pathologic conditions, enabling differential CAB antibody activities in normal versus disease microenvironments.

Randomized phase II study evaluating the addition of pembrolizumab to radium-223 in metastatic castration-resistant prostate cancer.

98 Background: Treatment (tx) options for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) to bone are limited. Radium-223 (R223) has demonstrated overall survival (OS) benefit, but objective clinical responses to R223 or the anti-PD1 checkpoint inhibitor (CPI) pembrolizumab (pem) are infrequent. As R223 may increase immunogenicity of mCRPC to bone and increase activity of CPI, we undertook a Phase 2 study to assess safety of the combination and differences in immune cell infiltrate in bone biopsies (bx) and preliminary clinical activity of R223 + pem vs. R223 alone. Methods: Eligibility required mCRPC to bone with no visceral metastases (mets) or lymph nodes > 2 cm, ECOG PS 0 or 1, Hgb ≥ 9 g/dL, and no prior R223 or CPI. Pts underwent bone bx at screening and at 8 wks. Pts were stratified by alkaline phosphatase ≥220 vs. < 220 U/L and high vs. low volume bony mets (CHAARTED criteria) and randomized 2:1 to receive R223 55 kBq/kg q4wks + pem 200 mg q3wks (Arm A) or R223 55 kBq/kg q4wks alone (Arm B). If restaging after 3 doses R223 showed at least stable disease, pts in Arm A continued pem alone until progressive disease (PD). Upon PD, R223 was resumed if no new visceral mets. Pts continued tx until clinical/radiologic PD, unacceptable toxicity or completion of 6 R223 doses. The primary endpoint was difference in CD4+ and CD8+ T-cell infiltrate in 8 wk vs. baseline bx; secondary endpoints were safety/tolerability, radiographic progression-free survival (rPFS) and OS. Exploratory endpoints included PSA response and rate of symptomatic skeletal events (SSEs). Results: Of 45 pts enrolled, 42 received study tx (29 Arm A, 13 Arm B) and were eligible for analysis. 21 pts in Arm A and 5 in Arm B had evaluable paired bone bx. Median fold-change of proportion of CD4+ T-cells/total cell count from baseline to 8 wks was 0.90 (range 0.0-26.6) in Arm A and 0.40 (0.0-13.0) in Arm B (P = 0.87); for CD8+ cells, median 0.67 (0.0-40.4) in Arm A and 0.40 (0.1-28.8) in Arm B (P = 0.77). Grade 3 treatment-related non-hematologic adverse events (AEs) occurred in 3 pts (10%) in Arm A (pneumonitis, diarrhea, AST increased); none in Arm B. Median rPFS was 6.7 mo (95% CI 2.7-11.0 mo) in Arm A and 5.7 mo (2.6-NR) in Arm B. Median OS was 16.9 mo (12.7-NR) in Arm A and 16.0 mo (9.0-NR) in Arm B. 3 pts (10%) in Arm A and 0 in Arm B had PSA reduction of ≥ 50%. SSE rate was 38% in Arm A and 54% in Arm B, with pathologic fractures in 0% of pts in Arm A and 23% in Arm B. Conclusions: In the 62% of treated pts with evaluable paired bx at baseline and after 8 wks, there was no evidence of increased CD4+ or CD8+ T-cell infiltration with R223 + pem. Additional biomarker analyses will be presented. This study revealed that R233 + pem did not result in unexpected AEs, but did not lead to prolonged rPFS or OS compared to R223 alone to support this two-drug combination in a biomarker-unselected population in this setting. Clinical trial information: NCT03093428.

Phase I/IB trial of sitravatinib (Sitra) + nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC) or other solid malignancies.

TPS365 Background: Sitra is a spectrum-selective receptor tyrosine kinase inhibitor (TKI) that targets TAM receptors (TYRO3, AXL, MERTK), VEGFR2, c-Kit, and c-MET. Sitra has shown antitumor activity in accRCC, and reduces type 2 tumor-associated macrophages, regulatory T-cells and myeloid-derived suppressor cells and enhances T cell–mediated antitumor immune responses. The combination of sitra with anti-PD1 immune checkpoint inhibitors (ICIs), such as nivo, has an acceptable safety profile and demonstrates efficacy across multiple tumor types, including accRCC (Msaouel et al. J Clin Oncol, 2020, abstr 612). Ipi enhances the efficacy of nivo through distinct but complementary pathways to those targeted by sitra. We hypothesize that the triple combination of sitra + nivo + ipi will lead to more potent antitumor responses. This study is designed to determine the optimal dose of sitra when combined with nivo + ipi, and assess the safety as well as the preliminary efficacy of this combination in accRCC, and potentially other cancers, that have shown favorable responses to nivo + ipi. Methods: This phase I/Ib study (NCT04518046) is evaluating sitra + nivo + ipi in frontline advanced or metastatic ccRCC or other solid malignancies. The primary endpoint of the trial is safety and tolerability of this regimen. Secondary endpoints include: objective response rate (RECIST 1.1), duration of response, progression-free survival, overall survival, and pharmacokinetic measurements. The phase I dose escalation portion of the trial will enroll approximately 30 pts with intermediate- or poor-risk accRCC by International Metastatic RCC Database Consortium (IMDC) criteria, who will receive escalating doses of sitra (starting dose 35 mg orally QD) following the Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design (Yuan et al. Clin Cancer Res, 2018), combined with nivo 3 mg/kg and ipi 1 mg/kg (NIVO3/IPI1) every 3 weeks (wks) for up to 4 doses, followed by maintenance nivo (240 mg every 2 wks or 480 mg every 4 wks). The phase Ib dose expansion cohorts will be initiated following identification of the recommended dose of sitra in combination with NIVO3/IPI1 and will enroll up to 31 pts for each of 2 cohorts: pts with intermediate-/poor-risk accRCC (Cohort A) and pts with favorable-risk accRCC (Cohort B). Pts will receive study treatment until disease progression, unacceptable adverse events, or pt withdrawal of consent. Future dose expansion cohorts may be added to include other solid tumors in which favorable activity has been previously demonstrated with nivo + ipi, such as metastatic urothelial carcinoma, melanoma, non–small-cell lung cancer, hepatocellular carcinoma, and colorectal cancer. The study is currently enrolling at 1 US site and additional sites may be added at dose expansion. At the time of the abstract submission, 3 pts have been enrolled. Clinical trial information: NCT04518046 .

Abstract SP116: B-cells and follicular T cells regulate responses to immune checkpoint inhibitors in breast tumors and melanomas

Abstract Triple Negative Breast Cancer (TNBC) makes up 10-15% of breast cancers, disproportionally affects African Americans, and if considered its own disease type, would rank as the #5 cause of cancer deaths in women in the USA each year. Among the most promising new therapeutic approaches for TNBC is immunotherapy using Immune Checkpoint Inhibitors (ICI). Many ICI trials for TNBC patients are underway with early results showing response rates to single agent ICI in the range of 10-20% in the metastatic setting. Thus, there is a good sign of efficacy, but the majority of TNBC patients still fail to respond, even despite the recent improvements made by combination regimens of ICI and chemotherapy. These findings illustrate a clear need for 1) improved biomarker(s) to identify the subset TNBC patients who will respond to current ICI-based regimens, and 2) improvements in ICI regimens that may include additional immune modulating therapeutics, and/or combinations with specific mechanistically chosen chemotherapeutics. Improving response rates of breast cancer patients to immune checkpoint inhibitors requires an understanding of mechanism of action of ICI, and robust in vivo models to further evaluate mechanisms and to empirically test new regimens in the preclinical setting first. In our prior work, we identified and credentialed mouse models with genomic and transcriptomic similarities to human TNBC, and in a subtype aware manner. In completing these studies, we found that the majority of TNBC mouse models reflect those human tumors with low tumor mutation burden (TMB), and these models had low immune infiltrates. In our efforts to model human TNBCs with elevated tumor mutation burdens we “mutagenized” our low TMB models into the range of high TMB human TNBC. We found that these mouse models with high tumor mutation burden had increased tumor infiltrating lymphocytes and were now responsive to anti-PD1 and anti-CTLA4 immune checkpoint inhibitors. Specifically, we discovered that in ICI sensitive mouse models, CD4+ T follicular helper cells and B cells coactivate one another and both are necessary for the full effects of the anti-tumor response to immune checkpoint therapy. We further used additional genetically engineered mouse models to discover a requirement for active antibody production as being needed for an effective anti-tumor response to immune checkpoint therapy. The direct and active involvement of B cells in response to ICI has recently been shown to also occur in melanoma patients. This suggests a broader role for B cells as being a key component of a coordinated anti-tumor immune response. In addition, we captured these mechanistic features within a small gene expression signature that we further demonstrated predicted response to ICI treatment in melanoma patients, to trastuzumab in HER2+ breast cancer patients, and to neoadjuvant chemotherapy in TNBC patients. To translate this knowledge to therapeutic advances, we are now using our mouse models to test if immunomodulators of B cells can improve T cell focused immunotherapies, some of which are showing promising results. In summary, the adaptive immune system is a critical component of response to multiple and diverse classes of drugs in breast cancer, including chemotherapy, HER2 targeting therapy, and ICI. Further studies aimed at boosting these responses could have a significant impact for many TNBC patients, and non-TNBC patients, as well. Citation Format: C Perou. B-cells and follicular T cells regulate responses to immune checkpoint inhibitors in breast tumors and melanomas [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 SP116.

Emerging Therapies in Relapsed and Refractory Hodgkin Lymphoma: What Comes Next After Brentuximab Vedotin and PD-1 Inhibition?

The standard of care for relapsed/refractory (r/r) Hodgkin lymphoma (HL) patients is autologous stem cell transplantation (ASCT) for patients in a first or second relapse. However, a significant number of patients with r/r HL are either medically ineligible for ASCT or relapse post-ASCT. In recent years, significant advances have been made in the management of r/r HL with the introduction of the anti-CD30 antibody-drug conjugate (ADC) brentuximab vedotin (BV) and the anti-PD1 checkpoint inhibitors (CPI) nivolumab and pembrolizumab. Nonetheless, despite excellent tolerability and high response rates, the large majority of patients will ultimately progress on these agents. Allogeneic hematopoietic cell transplantation (alloHCT) has offered a potentially curative option for these patients, but high rates of morbidity and mortality have limited its application, and disease relapse is also common post-alloHCT. Thus, effective therapy for HL patients who fail BV and CPI therapy remains an unmet need. This review will cover different treatment strategies for HL patients in this setting with a focus on emerging new therapies. Investigators have explored methods with the potential to restore sensitivity to BV and CPIs in patients who develop resistance. Additionally, promising new therapeutics are emerging, such as CD25-directed ADC therapy and CD30-directed chimeric antigen receptor (CAR) T cells. While no consensus guidelines exist for the management of HL patients refractory to BV and checkpoint blockade, potential novel strategies and therapeutics are currently under investigation in hopes of expanding the treatment landscape for this challenging patient population.

Anti-PD1 checkpoint inhibitor with or without chemotherapy for patients with recurrent and metastatic nasopharyngeal carcinoma

PurposeTo compare the efficacy and safety of anti-PD1 checkpoint inhibitor plus chemotherapy with anti-PD1 checkpoint inhibitor alone in recurrent and metastatic nasopharyngeal carcinoma (R/M NPC) progressing after first or subsequent-line therapy. Methods and materialsA total of 67 patients with recurrent and metastatic nasopharyngeal carcinoma from our hospital were included. All patients were sorted into two arms: anti-PD1 checkpoint inhibitor+ chemotherapy arm and anti-PD1 checkpoint inhibitor arm. We retrospectively estimated objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in patients of both arms. Chi-square test and Kaplan–Meier methodology were used to analyze. ResultsFrom September 2018 to March 2020, this research included 67 patients. For anti-PD1 checkpoint inhibitor+ chemotherapy arm, partial response and stable disease were observed in fourteen and 11 patients, respectively, for an ORR of 53.8%. For anti-PD1 checkpoint inhibitor arm, complete response and partial response were observed in one and 5 patients, respectively, for an ORR of 14.6%. The incidence of hyperprogressive disease was higher in the anti-PD1 checkpoint inhibitor group compared with anti-PD1 checkpoint inhibitor+ chemotherapy group (39.0% vs 3.8%, p<0.05). Univariable analyses discovered that 6-month PFS and OS benefits were observed for anti-PD1 checkpoint inhibitor+ chemotherapy arm compared to anti-PD1 checkpoint inhibitor arm (65.4% vs. 28.6%, P = 0.001; 100.0% vs. 73.5%, P = 0.014). ConclusionIn present study, we revealed that adding chemotherapy to anti-PD1 checkpoint inhibitor significantly improved 6-month PFS and OS for patients with R/M NPC progressing after first-line therapy. It warrants further study.

Increased Immunogenicity of a Minimally Immunogenic Tumor after Cancer-Targeting Near Infrared Photoimmunotherapy.

Simple SummaryNear-infrared photoimmunotherapy (NIR-PIT) is a highly selective cancer treatment that employs an antibody photoabsorber conjugate (APC) composed of a targeting monoclonal antibody (mAb) conjugated with a photoactivatable phthalocyanine-derivative dye. APC bound cancer cells are selectively destroyed upon NIR light exposure. Since NIR-PIT can induce selective immunogenic cell death, even in poorly immunogenic tumors, NIR-PIT has the potential to improve immunogenicity of tumor cells that could further enhance anti-tumor host immunity when combined with immune checkpoint inhibition. In this study, we showed that cancer-targeting NIR-PIT converted a minimally immunogenic tumor (MOC2-luc) into a highly immunogenic tumor by increasing the number and density of activated CD8+ T cells infiltrating into the tumor, leading to improved efficacy of the anti-PD-1 immune-checkpoint inhibitor. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective cancer treatment that employs an antibody photoabsorber conjugate (APC) composed of a targeting monoclonal antibody (mAb) conjugated with a photoactivatable phthalocyanine-derivative dye. Once injected and allowed to bind to a tumor, the APC is activated by local near-infrared light which kills cancer cells and induces a strong immune response in the tumor microenvironment by unmasking of new tumor antigens emerging from damaged tumor cells. Due to its ability to incite an immune reaction, even in poorly immunogenic tumors, NIR-PIT has the potential to enhance immunogenicity in tumors especially after immune checkpoint inhibition. In this study, we employ a poorly immunogenic MOC2-luc syngeneic tumor model and evaluate the efficacy of cancer-targeting CD44-targeted NIR-PIT. Increased infiltration of CD8+ T cells observed after NIR-PIT suggested an enhanced immune environment. Next, we evaluated tumor progression and survival after the combination of CD44-targeted NIR-PIT and short-term administration of an anti-PD1 immune checkpoint inhibitor (ICI) to further activate CD8+ T cells. Additionally, in mice in which the tumors were eradicated by this combination therapy, a re-challenge with fresh MOC2-luc cells demonstrated failure of tumor implantation implying acquired long-term immunity against the cancer cells. Combination therapy decreased tumor progression and prolonged survival significantly. Therefore, we concluded that NIR-PIT was able to convert a minimally immunogenic tumor unresponsive to anti-PD-1 ICI into a highly immunogenic tumor responsive to anti-PD-1 ICI, and this therapy was capable of inducing long-term immunity against the treated cancer.

NIVOLUMAB-INDUCED PULMONARY FIBROSIS: A NEW FINDING

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: The growth of personalized medicine has increased survival in aggressive cancers. Despite their improved side effect profile relative to early chemotherapy, monoclonal antibodies still feature many potentially severe side effects. Here, we present the first reported case of nivolumab-induced rapidly progressive pulmonary fibrosis. CASE PRESENTATION: A 65 year old gentleman with chronic respiratory failure requiring supplemental oxygen, a history of smoking, and stage IV supraglottic laryngeal cancer was started on nivolumab after progression of disease on platinum-based chemotherapy and radiation. Three months after starting nivolumab, honey-combing, traction bronchiectasis, and pulmonary fibrosis with lower lobe predominance was noted on computed tomography (CT) imaging during a hospital admission for dyspnea. (Image 1) Nivolumab was stopped, and oral corticosteroids were started. Despite this, the patient’s respiratory status continued to decline, requiring multiple hospitalizations. After admission for septic shock secondary to pneumonia, the patient suffered respiratory failure requiring intubation, which the patient declined and died with comfort care. DISCUSSION: Nivolumab is an anti-PD1 checkpoint inhibitor human monoclonal antibody approved for second-line use in squamous cell head and neck cancer with disease progression after platinum-based therapy. For this indication, median survival time is increased by 2.4 months. (1) Pneumonitis is a rare adverse effect of nivolumab, seen in 5-6% of patients. The median time of onset ranges widely from days to over a year. Most cases of pneumonitis are mild, and most cases improve or resolve completely. Features associated with worse outcomes include severity at presentation, underlying lung disease, poor lung function, and smoking history. Mainstay of treatment is high dose oral corticosteroids, with severe cases requiring intravenous steroids or additional immunosuppression such as infliximab. (2) Our patient had many of the poor prognostic factors for nivolumab-induced pneumonitis, but instead developed fibrosis. Pneumonitis has been reported many times, but to our knowledge this is the first evidence of pulmonary fibrosis caused by nivolumab. Potentially, the maelstrom of baseline conditions contributed to fibrosis rather than pneumonitis. CONCLUSIONS: Given the prevalence of chronic lung conditions, increasing use of nivolumab, and rapidly progressive nature of this case—from diagnosis to death in six weeks and poor response to steroids—consideration of pulmonary fibrosis as an adverse event of nivolumab may necessitate future considerations. Reference #1: Opdivo. [package insert]. New York, NY: Bristol-Myers-Squibb; 2014. Reference #2: Naidoo J, Wang X, Woo KM, et al. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2017;35(7):709-717. DISCLOSURES: No relevant relationships by Hazim Bukamur, source=Web Response No relevant relationships by Kendall Creed, source=Web Response My spouse/partner as a Consultant relationship with Abbvie Please note: $1-$1000 Added 05/27/2020 by Ebtesam Islam, source=Web Response, value=Consulting fee No relevant relationships by John Makram, source=Web Response No relevant relationships by Alexandra Wichmann, source=Web Response

1144P Clinical predictors of therapeutic benefit from anti-PD1 immune checkpoint inhibitors (ICI) in patients (pts) with metastatic uveal melanoma

1144P Clinical predictors of therapeutic benefit from anti-PD1 immune checkpoint inhibitors (ICI) in patients (pts) with metastatic uveal melanoma

1396P Development and validation of a host-dependent, PDL1-independent, biomarker to predict 6-month progression-free survival in metastatic non-small cell lung cancer (mNSCLC) patients treated with anti-PD1 immune checkpoint inhibitors (ICI) in the CERTIM cohort: The ELY study

Immunotherapy with ICI is active in a minority of NSCLC patients. The identification of new biomarkers of efficacy is needed. We studied the relationship between the metabolism of the patient and the effectiveness of ICI. Consecutive outpatients with mNSCLC had a nutritional assessment prior to initiate immunotherapy with either nivolumab or pembrolizumab. Rest energy expenditure (REE) was measured using indirect calorimetry and compared with the theoretical value provided by the Harris and Benedict formula. The hypothesis was that patients with normometabolism, thus able to induce active ATP-dependent lymphocyte activation would have a 2-fold improvement in 6-month progression free survival in comparison with patients with altered basal energy expenditure. A training set was used to find a cuttof for normometabolism definition and a validation set was prospectively recruited in two centers. Logistic regression model was applied to identify factors associated with 6-month PFS and a Cox model was used for survival. In the training cohort (39 patients, one center), normometabolism defined as measured REE of 90-110% of theoretical REE, had better 6-month PFS (54% versus 12%; odds ratio : 8.32; IC95 [1,40-65,99]; p=0.01) and presented a trend for improved overall survival (HR 2.15 ; IC95 0.994-4.661 ; p=0.05). In the validation cohort (100 patients, 2 centers), normometabolic patients had better 6-month PFS (56% versus 29%; odds ratio: 3.09 IC95 [1,21 - 8,11]; p=0.01) and improved survival (HR 2.37; IC95 1.25-4.49; p=0.008). The positive predictive value was 71% and the negative predictive value was 56%, Sensitivity 76% Specificity 50%. The measurement of REE prior to ICI initiation improves the identification of mNSCLC patients who will experience favorable 6-month PFS and survival.

Abstract 1993: A comprehensive benchmarking of paired whole exome and transcriptome biomarker analysis of response to cancer immunotherapy

Abstract Recent advances in cancer immunotherapy have revolutionized cancer treatment. Notably, pembrolizumab - an anti-PD1 checkpoint inhibitor - has been approved as first-line treatment for metastatic non-small cell lung cancer. Clinical response to checkpoint inhibitors has been demonstrated in other cancer types; however, durable response is not observed in all patients. As a result, development of new biomarkers for response to checkpoint inhibitors has become an active area of research. Due to the complexity of the anti-tumor immune response, a single biomarker may not accurately predict patient response to immunotherapy. In parallel, dramatic decreases in the costs of next generation sequencing (NGS) have enabled broad whole exome sequencing (WES) and whole transcriptome sequencing (WTS)-based studies, enabling a new phase in both academic and clinical cancer research. Despite the proven utility of NGS-based biomarker analysis, the accuracy of combined WES/WTS results compared to other assays, specifically in clinical tumor tissues, has not been demonstrated. In this study, we perform comprehensive benchmarking of several immuno-oncology (IO) biomarkers on cell lines, fresh frozen tumor tissues, and formalin-fixed paraffin-embedded (FFPE) tumor tissues. WES and WTS libraries were generated using Illumina Nextera Flex for Enrichment, TruSight Oncology, and TruSeq Stranded Total RNA library prep methods, and sequenced on a NovaSeq 6000. Using an internally developed bioinformatics pipeline, the accuracy of several IO biomarker measurements was evaluated. Specifically, we investigated the performance of tumor-only (T) and/or paired tumor-normal (TN) WES/WTS in assessing tumor mutational burden (TMB), microsatellite instability (MSI), tumor purity, copy number variants (CNV), human leukocyte antigen (HLA) type, fusions, and tumor infiltrating lymphocytes (TILs) levels, among other features. Our benchmarking results demonstrated correlations of 0.99 and 0.98 for TMB as measured by TN and T, respectively (truth: FOCR reported TMB); 100.0% PPV and NPV for MSI status as measured by both TN and T (truth: MSI-PCR); 0.86 correlation for tumor purity estimates based on TN (0.64 based on T; truth: cell-line titration levels); 100% PPV for both TN and T CNV calling (truth: ddPCR); 92% accuracy for both TN and T HLA typing (truth: IHW HLA types); 92.9% sensitivity for fusion calling (truth: ddPCR); and R2 values of 0.87, 0.70, and 0.48 for CD19+, CD4+, and CD8+ TIL levels, respectively (truth: FACS). Taken together, this study demonstrates WES/WTS can not only be utilized for broad exome- and transcriptome-wide biomarker discovery, but can also be an accurate, comprehensive alternative to iteratively testing IO biomarkers. Future studies should further standardize assay and analysis approaches for NGS-based biomarker measurements to ensure consistent and accurate reporting. Citation Format: Mahdi Golkaram, Michael Salmans, Raakhee Vijayaraghavan, Shannon Kaplan, Robert Haigis, Joyee Yao, Kristina Kruglyak, Li Liu, Traci Pawlowski, Sven Bilke, Shile Zhang. A comprehensive benchmarking of paired whole exome and transcriptome biomarker analysis of response to cancer immunotherapy [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 1993.

Abstract 6512: Tissue engineered metastases to improve cancer immunotherapy

Abstract Background: Radiotherapy can induce the abscopal effect when combined with immune checkpoint inhibition. The main limitations to this treatment are the lack of control over the tumor microenvironment and the tumor is not amendable for radiosurgery. To overcome this, we hypothesize that using ex-vivo engineered cancer metastases treated with radiotherapy can improve the impact of the abscopal effect, as the immune cascade reaction is radiotherapy dose dependent and tumors can be exposed to higher amounts of radiation ex-vivo without the risk of radiation toxicity using our tissue engineered metastases model to boost immune response. Methods: Using B16F10 as a model, we first engineered B16F10 lung metastasis ex-vivo using decellularized rat lung biomatrix scaffolds. The engineered lung metastases were then lethally irradiated with 100 Gy of radiotherapy. The cells were then injected subcutaneously into tumor bearing C57BL6 mice in combination with anti PD-1 checkpoint inhibitor. Experimental groups included: no treatment, anti PD-1 only, cell lysate with and without anti PD-1, and irradiated engineered metastases with and without anti PD-1. All the mice were inoculated with 50,000 plastic grown B16F10 cells. On days 3, 6, and 9 the mice received immunotherapy and radiotherapy combinations based on their respective groups. The tumors were then analyzed by flow cytometry and IHC staining for different T cell populations. Results: We successfully engineered B16F10 lung metastasis ex vivo. We then demonstrated that mice treated irradiated engineered lung metastasis had significantly better survival than any other treatment arms with median survival twice that of irradiated cells (P &amp;lt;0.01). Correlative studies showed that mice that received irradiated engineered metastasis had increased CD8+ cells and lower Treg cells when compared to other experimental groups. This indicates that engineered metastasis increased immune activation and response to tumor. Conclusions: Our data demonstrates that engineered metastases can indeed improve cancer immunotherapy and induce a robust abscopal/vaccine effect. Citation Format: Nikhila Reddy Sultanpuram. Tissue engineered metastases to improve cancer immunotherapy [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 6512.

Abstract CT130: Evidence for synergistic immune responses in the first-in-human (FIH) combination of B cell-activating immunotherapy (IO) with anti-PD1 immune checkpoint inhibitor nivolumab (N) as 2nd-line therapy in patients (pts) with advanced non-small cell lung cancer (aNSCLC)

Abstract Introduction: While combined immunotherapeutic activation of B and T cells is predicted to synergistically enhance both humoral and cell-mediated immunity, this has not been previously tested in human cancer patients. To assess this, we conducted the FIH trial combining B cell-activating IO (CIMAvax-EGF (C)) with T cell-activating IO (PD-1 blockade with nivolumab (N)). C activates B cells to produce endogenous anti-epidermal growth factor (EGF) antibodies (Abs) that deplete EGF from circulation. As a single agent maintenance therapy in aNSCLC, C prolonged overall survival (OS) in a randomized phase III trial. We now present immune correlates of improved OS with this novel combination. Methods: We reported safety and preliminary efficacy data from 13 pts from the phase I study of C+N (AACR 2019). Serial blood samples were analyzed by Luminex for dynamic changes in circulating cytokines and proteins implicated in EGF signaling, and by flow cytometry for peripheral blood mononuclear cell immunophenotype. Cox regression analysis was used to analyze association with OS. Results: 71% of pts achieved anti-EGF Ab titers of &amp;gt;1:4000 after 3 doses of C, compared to historical controls of 39% with C alone. Baseline increase in CD8+ naive T cells, memory B cells, and decrease in MDSC and Th17 T cells all significantly correlated with better OS. Baseline increase of inflammatory cytokines/markers (IL7, IL15, IFNα, IL8, sCD40L and CRP) significantly correlated with worse OS. Despite enrichment for pts with tumor proportion score (TPS) PD-L1 0%, median OS (mOS) of the intent-to-treat population (pts who received at least 1 dose of C+N, n=13) was 13.7 months (mo) vs. 9.9 mo in Checkmate 057 aNSCLC pts with tumor proportion score (TPS) PD-L1 &amp;lt;10%. mOS of per-protocol pts (all 4 loading doses of C+N given over 8 weeks, n=11) was 18.5 mo. In contrast to Checkmate 057 results, where OS benefit of N favored aNSCLC with KRAS mutation (KRASm), C+N showed better mOS of 22.4 mo in EGFR/ALK/KRAS wildtype (wt) pts versus 12.3 mo in KRASm/STKwt pts. Conclusion: This study provides evidence for synergistic effects of combining B and T cell activating IO in aNSCLC pts. C+N generated higher anti-EGF titers in more pts at an earlier time point vs. C alone, which is the first demonstration in pts of enhancement of Ab responses by immune checkpoint blockade. Immune analysis identified new specific immune cell populations and inflammatory markers that significantly correlate with OS with C+N that have not been previously identified with C or N as single agents. C+N improved OS compared to historical controls of aNSCLC pts receiving N in phase III trials. Of particular note, C+N showed better OS in pts with EGFR/ALK/KRAS wt aNSCLC versus KRASm/STKwt pts. The Phase II portion of the study is ongoing. Citation Format: Tania Crombet, Jason Muhitch, Circe Mesa, Rachel Evans, Danay S. Hernandez, Patricia L. Luaces, Zaima Mazorra, Orestes Morales, Carlos Cedeno, Aileen Cinquino, Daniel T. Fisher, Kelvin Lee, Mary Reid, Grace Dy. Evidence for synergistic immune responses in the first-in-human (FIH) combination of B cell-activating immunotherapy (IO) with anti-PD1 immune checkpoint inhibitor nivolumab (N) as 2nd-line therapy in patients (pts) with advanced non-small cell lung cancer (aNSCLC) [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 CT130.

Abstract 5571: Turning up the heat on pancreatic ductal adenocarcinoma via inhibiting vasoactive intestinal peptide signaling

Abstract Pancreatic ductal adenocarcinoma (PDAC) constitutes more than 90% of all pancreatic cancers and has a 5-year survival rate of only 5-7%. A dense stroma, an immunosuppressive tumor microenvironment (TME) and scarce tumor infiltrating T cells, contribute toward the poor responsiveness of PDAC to conventional and FDA-approved checkpoint therapies. In this study, we show that vasoactive intestinal peptide (VIP) signaling is a novel immune checkpoint pathway in PDAC, which when inhibited in combination with anti-PD1 checkpoint inhibitor, significantly decreases tumor burden and enhances T cell infiltration in mouse models of PDAC. VIP is a 28-amino acid neuropeptide secreted at the nerve terminals, pancreas and the GI tract, and is commonly associated with regulating gut motility and blood pressure. Interestingly, VIP is also secreted by immune cells and is known to have immunosuppressive properties such as decreasing T cell proliferation and polarizing T cells towards Th2 phenotype. Intriguingly, according to the cancer genome atlas (TCGA), human exocrine pancreatic cancers expresses the highest level of VIP mRNA expression when compared to other solid malignancies. Similarly, we have generated preliminary data that shows enhanced VIP levels both systemically and locally in mouse models of PDAC and in human PDAC patients. Thus, taking all this into consideration, we hypothesized that enhanced VIP signaling is a potential mechanism of immune escape in PDAC and that inhibiting VIP signaling either alone or in combination with checkpoint inhibitors would significantly enhance treatment response in mouse models of PDAC. We tested the effect of inhibiting VIP signaling by using a VIP receptor antagonist (VIPR antagonist) in orthotopic mouse models of PDAC, where luciferase transfected KPC cells (mouse PDAC cell line), were implanted in the tail of the pancreas. Mice were then treated with VIPR antagonist and/or anti-PD1 seven days after tumor implantation. Our results showed that the combination treatment significantly reduced tumor burden and growth rate, as well as, enhanced the infiltration of both CD4+ and CD8+ T cells into the tumor microenvironment (as per immunohistochemistry of tumor tissues). Furthermore, analysis of tumor infiltrating T cells via Nanostring analysis showed that the combination treatment also significantly enhanced levels of IFN gamma and TNF alpha secreting T cells and costimulatory and effector molecules, including CD27 and FasL. In summary, we have identified that VIP signaling is a novel and targetable immune checkpoint pathway in PDAC, which when inhibited in combination with checkpoint inhibitors, significantly improves treatment response in mouse PDAC models. As the VIP sequence is conserved across different species including mouse and human, and since we have observed VIPR antagonists stimulate proliferation of human T cells, there is an increased potential for clinical translation of VIPR antagonists in the treatment of human PDAC. Citation Format: Sruthi Ravindranathan, Brandon Ware, Mohammad Zaidi, Jingru Zhu, Rohan K. Dhamsania, Shuhua Wang, Yiwen Li, Ishani H. Rao, Susan N. Thomas, Gregory B. Lesinski, Bassel El-Rayes, Edmund K. Waller. Turning up the heat on pancreatic ductal adenocarcinoma via inhibiting vasoactive intestinal peptide signaling [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 5571.

Abstract 2287: Bispecific anti-PD1 checkpoint inhibitors antibodies (BiCKI), an optimized platform designed to tackle anti-PD-(L)1 primary and secondary resistance mechanisms

Abstract Although Anti PD(L)1 therapy lead to impressive therapeutic responses by reinvigorating T cells, primary and secondary resistances occur de novo or during treatment impeding the full efficacy of the drug. To tackle this resistance mechanisms and reduced the immunotoxicity of combination therapy, we designed a 2nd generation of anti-PD1 antibody by fusing immune protein to the Fc portion of the antibody, named BiCKI®. The anti PD1 will more selectively drive the immune active drug on antigen-experienced (PD1+) T cells, through cis-targeting mechanism. These bifunctional molecules were designed with an optimized anti-PD1 backbone for bispecific format, fused to an active protein domain to the C-ter of heavy and/or light chains. Different protein candidate were successfully fused to the optimized anti-PD1, such as cytokines, costimulatory molecules, or dominant negative receptors with PD1/PDL1 full antagonistic activity. In contrast to combination, BiCKI® antibodies enable the simultaneous dual-binding specificity in a single drug allowing a synergistic activation. Each BiCKI® is selected on its synergistic capacity to re-activate of anti-tumor T cell responses or TCR signaling in cell-based assays. Bispecific antibody development in clinic has been hampered by difficult manufacturing process, reduced pharmacokinetic (PK) and drug exposure. Both anti PD-1 CDRs and VH/VL framework sequences were carefully selected and optimized for bioproductivity and biostability of the molecule. A 2 to 15-fold increased productivity in mammalian cells was observed versus the non-optimized anti-PD1 antibody or other anti-PD-1 bispecific backbones as Pembrolizumab or Nivolumab. We also evaluated the impact of the Fc isotype,linker flexibility and affinity of the fused compound on the PK profile of different bispecifics fused to costimulatory molecules or cytokines. The IgG isotype with reduced FcgR binding property, of the anti-PD-1 backbone was associated with a better PK profile with some exceptions for cytokine. The presence or length of a linker between Fc domain and the fused protein has a small impact the PK and drug efficacy. More importantly, the affinity of the fused compound has an impact the PK profile of BiCKI® For example, the anti-PD-1 fused to wild-type IL-7 cytokine possesses a high affinity for the CD127/CD132 receptors but display a reduced drug exposure both in mouse and cynomolgus. This potential difficulty was solved with further improved products including IL-7 mutants having reduced affinity for CD127 and/or CD132. While significant correlation between IL7 affinity and PK has been observed, increased PK and drug exposure could be achieved using optimized combination of Fc isotype a linker length design and BiCKI-IL7 mutants retaining significant IL7R signaling. Conclusion: Our BICKI® platform was designed to overcome major hurdles of bispecific antibody development, we improved its manufacturability and drug exposure by selectively designing the structure of bispecific antibodies. By fusing costimulatory molecule, cytokines or dominant negative receptor to the anti PD-1 blocking antibody, we can generate and select various efficient bispecific molecules acting in synergy to counteract primary and secondary resistance mechanisms of anti-PD(L)1 therapies. Citation Format: Caroline Mary, Aurore Morello, Virginie Thepenier, Géraldine Teppaz, Justine Durand, Nicolas Poirier. Bispecific anti-PD1 checkpoint inhibitors antibodies (BiCKI), an optimized platform designed to tackle anti-PD-(L)1 primary and secondary resistance mechanisms [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 2287.

Abstract 391: Lrg1 blockade modulates the tumor immune microenvironment and improves the efficacy of cancer therapeutics

Abstract Although the use of checkpoint inhibitors and adoptive T cell therapy have been reported in multiple cancers resulting in a plethora of clinical trials, the efficacy of these therapeutic strategies is often limited by the presence of impaired vasculature in the tumour mass. Indeed, in solid tumors, blood vessels are dysfunctional, leaky and poorly perfused, and thwart not only the efficacy of systemically derived drugs but also the extravasation of T cells, promoting an immunosuppressive microenvironment. Leucine-rich alpha-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that is associated with pathogenic neovascularization, autoimmune diseases, chronic inflammation, and is significantly up-regulated in many solid cancers. We have observed that treatment with a LRG1 function-blocking antibody (15C4) significantly limits growth of solid tumors inducing vessel normalization and functionality. In the present study, we aim to investigate if LRG1 blockade enhances an immunostimulatory milieu, making tumors more responsive to current immunotherapies. Murine melanoma cells harbouring the internal influenza nucleoprotein antigen, NP68, were grafted subcutaneously before antigen-specific F5B6 CD8+ T cells were also transferred. Interestingly, the combination with 15C4 promoted a greater reduction in tumor growth rate. Moreover, not only was the number of donor CD8+ T cells significantly higher when delivered with 15C4, but also the total number of CD3+ T cells was increased following combination therapy, suggesting a more robust host-derived lymphocyte trafficking. As blocking LRG1 normalizes the tumor vasculature and enhances T cell extravasation, we then evaluated whether 15C4 could improve delivery and efficacy of an anti-PD1 checkpoint inhibitor. As monotherapies, both 15C4 and anti-PD1 antibodies induced a marked reduction in tumor volume but when the two were combined, a significant additive effect was also observed. Histological analysis revealed that the combination therapy was associated with a significantly higher number of activated CD8+ T cells, together with enhanced expression of Granzyme B. Current studies are investigating whether the observed boost in cytotoxic T cell density and functionality is a direct consequence of vessel normalization or whether LRG1 blockade is able to modulate the tumour immune microenvironment at different levels: for example, FACS analysis of tumour-infiltrating leukocytes revealed a reduction in the percentage of regulatory T cells after dual therapy, while histological analysis suggested an increase in the number of M1 macrophages. These data show that LRG1 blockade orchestrates a shift in the tumour microenvironment from being immune silent to immune active and, therefore, might represent a novel tool to enhance the efficacy of cancer therapies. Citation Format: Carlotta Camilli, Camilla Pilotti, Marie N. O'Connor, David Kallenberg, Markella Alatsatianos, Angharad H. Watson, Julia Ohme, Athina Dritsoula, Ann Ager, Stephen E. Moss, John Greenwood. Lrg1 blockade modulates the tumor immune microenvironment and improves the efficacy of cancer therapeutics [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 391.