Durable Response Rate Research Articles

Short-course pembrolizumab and continuous afatinib therapy for recurrent or metastatic head and neck squamous cell carcinoma: a real-world data analysis

ObjectivesThe optimal duration of anti-PD-1 for cancer therapy has not been tested, especially when using combination therapy. Epidermal growth factor receptor (EGFR) pathway blocker was the top compound that enhanced T-cell killing of tumor cells in a high-throughput immune-oncology screen, possibly by stimulate the antigen presentation machinery and other mechanisms. We explored the effect of combination of EGFR inhibition with a short course of anti-PD-1 therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).MethodWe analyzed the effect of a short course of anti-PD-1 with continuous afatinib on the survival of a real-world cohort of R/M HNSCC patients. Patient characteristics, treatments, efficacies, and toxicities were reviewed and recorded for analysis.ResultsFrom November 2016 to May 2018, 51 consecutive patients received pembrolizumab and afatinib. The cutoff date was June 30, 2022. The most common toxicities (all grades) were diarrhea (62.7%), skin rash (43.1%), mucositis (31.4%), and paronychia (23.5%). The objective response rate was 54.9% (95% confidence interval [CI] 40.3–68.9%). Median progression-free survival was 5.9 months (95% CI: 4.4–7.6 months), and the median overall survival was 10.5 months (95% CI: 6.8–16.5 months). The 12-month, 24-month, 36-month, and 48-month survival rate was 47.0%, 22.5%, 17.7%, and 12.6% respectively.ConclusionsThis retrospective study showed that short course pembrolizumab with afatinib therapy has acceptable efficacy in R/M HNSCC patients. The durable response and long-term survival rates were similar to prospective clinical trials. Short course anti-PD-1 therapy, especially in combination with EGFR blocker, is worth for further prospective study.

Efficacy and safety of tisagenlecleucel in adult Japanese patients with relapsed or refractory follicular lymphoma: results from the phase 2 ELARA trial

BackgroundTisagenlecleucel yielded a high durable response rate in patients with relapsed/refractory (r/r) follicular lymphoma (FL) in the global phase 2 ELARA trial. Here, we report the efficacy, safety, and cellular kinetics of tisagenlecleucel in a subgroup of Japanese patients with r/r FL from ELARA.MethodsELARA (NCT03568461) is a global single-arm trial of tisagenlecleucel in patients with r/r FL who received ≥ 2 prior lines of therapy. The primary endpoint was the complete response rate (CRR), and the secondary endpoints were the overall response rate, duration of response, progression-free survival, overall survival, safety, and cellular kinetics.ResultsAs of March 29, 2021, nine Japanese patients were enrolled and received tisagenlecleucel with a median follow-up of 13.6 months (range, 10.5‒19.3). Per independent review committee, CRR was 100% (95% CI 63.1‒100). Within 8 weeks of infusion, cytokine release syndrome (CRS) of any grade was reported in 6 patients (66.7%); however, no grade ≥ 3 CRS or any grade serious neurological events or treatment-related deaths were observed.ConclusionTisagenlecleucel showed high efficacy and manageable safety in adult Japanese patients with r/r FL. Moreover, the clinical outcomes were similar to the global population, which supports the potential of tisagenlecleucel in Japanese patients with r/r FL.

Longitudinal, Real-World Data Reveal Treatment Effectiveness in Idiopathic Multicentric Castleman Disease and Support Current Treatment Guidelines

Background: Idiopathic multicentric Castleman disease (iMCD) is an immunologic disorder with unknown etiology that is diagnosed in approximately 1200 individuals in the US annually. Presentation is heterogeneous - ranging from mild/moderate constitutional symptoms to severe multi-organ dysfunction. Treatment guidelines were developed by an international expert panel in 2017 based on the review of a limited number of clinical trials and small case series. Siltuximab, a monoclonal antibody against interleukin-6 (IL6) approved for the treatment of iMCD, is recommended first-line based on evidence from its phase II trial. High-dose steroids and cytotoxic chemotherapy are recommended for patients with severe disease who progress on anti-IL6 therapy. For patients with mild/moderate disease not responding to IL6 blockade, rituximab +/- immunomodulators is recommended. While concurrent steroids are recommended in some cases, steroid monotherapy is discouraged. Limited data exist on the effectiveness of these agents beyond siltuximab. Herein, we evaluate treatment regimens administered to a cohort of 83 iMCD patients with longitudinal treatment and response data. Methods: A review of cases in the ACCELERATE natural history registry by a panel of experts led to the identification of 83 patients with confirmed iMCD. Longitudinal treatment and response data were abstracted from medical records. Durable treatment response was defined as the best response according to the change in the proportion of abnormal clinical/laboratory criteria sustained for at least 1 year. Severity at the time of treatment initiation was defined as ≥2 of renal failure, fluid accumulation, severe anemia, pulmonary involvement, or hospitalization. Survival analysis for time-to-next-treatment, a proxy for time to treatment failure, was performed on regimens categorized in the guidelines: siltuximab +/- best supportive care (BSC), tocilizumab +/- BSC, rituximab +/- BSC, chemotherapy +/- other agents, and steroid monotherapy. BSC includes steroids, transfusions, and other supportive modalities. Log rank test was used to determine differences across treatment regimens, and pairwise comparisons were Bonferroni corrected. Results: Approximately half (47%) of the patients were female, with a mean (SD) age at diagnosis of 35.9 (16.2). A total of 261 regimens were administered across the cohort. Of the 41 patients who received siltuximab +/-BSC, 44% (N=18) achieved a durable response. Durable response rates to other treatments included: tocilizumab +/-BSC: 41% (7/17); rituximab +/-BSC: 23% (6/26); chemotherapy +/-BSC: 38% (8/21); steroid monotherapy: 6% (2/32). Steroid monotherapy was significantly less likely to induce a durable response than siltuximab +/-BSC (p=0.02). Notably, response rates were significantly lower across modalities in severe compared to mild/moderate disease (p=0.004). We also found that the treatment regimen significantly predicts time-to-next-treatment (p<0.0001, Figure 1). Median time-to-next-treatment for siltuximab +/-BSC is 742 days (95% CI: 1.26, no upper limit), tocilizumab +/-BSC is 689 days (234, no upper limit), rituximab +/- BSC is 153 days (116, 399), chemotherapy +/- other agents is 463 days (107, 791), and steroid monotherapy is 64 days (36,129). Pairwise comparison demonstrated that siltuximab +/-BSC, tocilizumab +/-BSC, and chemotherapy each have a significantly longer time-to-next-treatment compared with steroids (p<0.05). Further, siltuximab +/- BSC also had a significantly longer time-to-next-treatment than rituximab +/-BSC (p=0.02). There were no other differences between regimens. Discussion: Though guidelines were developed in 2017, this is the first systematic assessment of iMCD treatment regimens included in these guidelines. We found differences in durable response rates and in time-to-next-treatment between regimen approaches. Patients on steroids alone require additional drug-intervention a median of 2 months after treatment start, while patients treated on siltuximab +/-BSC remained on treatment for a median of 2 years before additional interventions were added. Our results support current recommendations to administer siltuximab first-line and limit steroid monotherapy use. These results also demonstrate that additional agents are needed for refractory patients, who have few options and are at risk of death due to progression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

G-CSF Administration Is Associated with Worse Treatment Response and Survival after CAR T-Cell Therapy

Background: Chimeric antigen receptor T (CAR T)-cell therapy has led to unprecedented responses in patients with relapsed/refractory non-Hodgkin's lymphoma and heavily treated multiple myeloma. Despite impressive and relatively durable response rates, CAR T-cell therapy does not work for all patients and most patients tend to relapse. Recent correlative data from patients with decade-long remissions after CAR T-cell therapy showed that the initial response phase is driven by CD8+ CAR T-cells with a long-term remission phase dominated by CD4+ CAR T-cell phenotypes [Melenhorst JJ et al. Nature, 602(7897), 503-509]. Preclinical data has shown that G-CSF directly influences the effector function of cytotoxic CD8+ T cells and may lead to reduced reactivity [Franzke A et al. (2003) Blood, 102(2), 734-739 & Bunse CE et al. (2016). Clinical & Experimental Immunology, 185(1), 107-118]. Studies outlining the prognostic impact of G-CSF among patients treated with CAR T-cell therapy remain limited. There are no consensus guidelines for management of prolonged cytopenia using growth factor support, with wide variations in guiding practice amongst physicians or institutions. In this study, we recorded the utilization of G-CSF in a cohort of 80 consecutive patients treated with CAR T-cell therapy at our institution. We analyzed its potential impact on treatment response and survival after CAR T-cell therapy. Methods: This is a retrospective analysis of consecutive adult patients with an underlying B cell non-Hodgkin lymphoma (n=60) or multiple myeloma (n=20) treated with CAR T-cell therapy from 2016-2022. Baseline characteristics, laboratory measurements and clinical events following CAR T-cell therapy were collected by review of patients' electronic medical record. Medication records were reviewed to determine exposure to G-CSF, starting on day +1 through day +30 following CAR T-cell infusion. We used a chi square test or Fisher's exact test to compare proportions between groups. We calculated unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS) and compared survival between the groups using the Mantel Cox log rank test. Results: Of 80 patients treated with CAR T-cell therapy, 76.2% (61/80) developed neutropenia with nadir ANC <500/uL before day +30. The median time to onset of neutropenia was +1 day, and 26.2% (21/80) of patients were neutropenic at the time of CAR T-cell infusion. In this cohort, 68.7% (55/80) of patients received G-CSF for management of severe neutropenia between days +1 and +30. Median time to initiation of G-CSF was 4 days (range 1-23 days) after treatment. Use of G-CSF did not decrease median length of stay compared to patients who did not receive G-CSF (20.5 vs 19 days). Administration of G-CSF was associated with worse treatment response at day 30, with only 65.5% (36/55) of patients in the G-CSF group attaining complete or partial response, compared to 88% (22/25) of patients in the non-G-CSF group with partial response or better (p=0.04). Patients who received G-CSF had significantly worse PFS (4.43 vs 63.1 months; p=0.01 with HR 2.23 95% CI 1.2 to 4.123 and OS (13.7 vs 67.8 months; p=0.001 with HR 3.62 95% CI 1.88 to 7.02) compared to patients not treated with G-CSF. On multivariate analyses, differences in survival with G-CSF use persisted despite adjusting for prior lines of therapy, HSCT status, development of CRS and underlying disease for PFS (adjusted HR 3.66; 95% CI 1.67-8.03) and OS (adjusted HR 4.66; 95% CI 1.70-12.76). Although patients with underlying myeloma had worse median OS when compared to patients with lymphoid malignancy (10.8 vs 24.8 months, respectively), both groups had significantly worse OS when compared to patients in the non-G-CSF group (67.8 months, p=0.001 and p=0.002 respectively). Among patients who received G-CSF, three or more prior lines of therapy was associated with worse OS (11.5 months), but patients who received <3 prior lines of therapy also had a significantly worse OS compared to the non-G-CSF group (p=0.03; HR 3.3 with 95% CI 1.1 to 9.8). Conclusion: In this single institution retrospective study, administration of G-CSF within 30 days of CAR T-cell infusion is associated with worse treatment response, PFS and OS irrespective of underlying disease, prior lines of therapy or HSCT status. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BRUIN CLL-314: A Phase III Open-Label, Randomized Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Background: Covalent Bruton's tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Two covalent BTKi, ibrutinib and acalabrutinib, are currently approved for CLL/SLL and a third, zanubrutinib, is pending review. Covalent BTKi share pharmacologic liabilities (e.g., low oral bioavailability, short half-life), which collectively may lead to suboptimal BTK target coverage (Wang et al. Blood 2021;138:381), ultimately manifesting as acquired resistance in some patients (Mato et al. Lancet 2021;397:892-901). Additionally, tolerability issues limit long-term dose intensity and may compromise efficacy. Novel agents that address both intolerance and resistance while also improving efficacy are needed. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates (ORR) and was well tolerated in patients with CLL/SLL regardless of prior therapy (including covalent BTKi), number of prior lines of therapy, BTK C481 mutation status, or reason for prior covalent BTKi discontinuation (Mato et al. Lancet 2021;397:892-901). Based on the efficacy of pirtobrutinib in patients previously treated with covalent BTKi, we hypothesized that pirtobrutinib could be a more effective BTKi when used as initial BTK therapy. In this global, phase 3, open-label, randomized study, we aim to compare the efficacy and tolerability of pirtobrutinib vs ibrutinib in patients with CLL/SLL. Study Design and Methods: BRUIN CLL-314 is a global, phase 3, open-label, randomized study comparing pirtobrutinib with ibrutinib. Approximately 650 BTKi-naïve patients, either treatment-naïve or previously treated with other agents, will be randomized 1:1 to receive daily 200 mg pirtobrutinib (recommended phase 2 dose from the BRUIN study) or 420 mg ibrutinib as continuous monotherapy. Randomization will be stratified by del(17p) status (present vs not present) and number of prior lines of therapy (0 vs 1 vs ≥2). Eligible patients are adults ≥18 years with a CLL/SLL diagnosis and requirement for therapy per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria. Key exclusion criteria include prior exposure to BTKi, use of certain concomitant therapeutics including anticoagulants such as warfarin and other vitamin K antagonists, significant cardiovascular disease, active infections, and other clinically significant conditions. The primary objective is to establish non-inferiority of pirtobrutinib vs ibrutinib by comparing the ORR in accordance with iwCLL guidelines assessed by an independent review committee. Superiority of pirtobrutinib vs ibrutinib in event-free survival and progression-free survival are key secondary objectives. Other endpoints include duration of response, overall survival, time-to-next treatment, safety and tolerability, and patient-reported outcomes. Trial efficacy and safety will be monitored by an independent data monitoring committee. This global study is currently enrolling patients (NCT05254743).

Multi-Omics Analysis of Human Mesenchymal Stem Cell Guides Perinatal MSC Based Cellular Therapy for Splenectomy-Nonresponsive Refractory Immune Thrombocytopenia: A Phase I Clinical Trial

Mesenchymal stem cells (MSCs) are a heterogeneous population with the capacities of self-renewal, tissue regeneration and immunoregulation, which have attracted intensive attention for their potential application in the treatment of various immune disorders. However, the immunosuppressive efficacy of these therapies based on MSC products has not been thoroughly characterized, which may lead to inconsistent outcomes of MSC therapy in clinical trials. Cellular senescence is a state that imposes permanent proliferative arrest on cells in response to various types of stress and damage. Evidence suggests that aging MSCs tend to have a compromised immunosuppressive capability for inhibiting T cells. However, the underlying cellular and molecular mechanisms are poorly understood. It is also unknown whether the proportions and states of senescent cells in MSC products derived from various donors and different culture passages is associated with dissonant outcomes across clinical trials of MSC therapies. Immune thrombocytopenia (ITP) is an autoimmune disease characterized by immune-mediated destruction of circulating platelets (PLTs) and suppression of PLT production. It has been reported that autoantibody-coated PLTs undergo accelerated clearance through the spleen macrophage. However, anti-PLT antibodies are detected in less than 50% of patients, which raises the possibility of alternative mechanisms of PLT destruction. In line with this, splenectomy, which removes the primary site of PLT destruction and inhibits B-cell-mediated autoantibody production, has been shown to be the most effective therapy for steroid-refractory or steroid-dependent ITP and offers the highest rate of durable response (60% to 70%) compared with other therapies. Nevertheless, 30% to 40% of refractory ITP patients still show no response to splenectomy, indicating a B-cell-independent pathogenic mechanism. Abnormal function of T cells has been reported in ITP patients, which could collectively drive the autoimmune process. Therefore, the immune mechanism underpinning ITP should be further investigated. Additionally, it is of great value to explore new therapeutic options, such as MSC-based cellular therapy, especially for splenectomy-nonresponsive refractory ITP. Here, we performed a single-cell transcriptomic analysis of clinically used MSCs derived from adipose tissue (AD), the bone marrow (BM), the placental chorionic membrane (PM) and the umbilical cord (UC). The transcriptomic profiles of a total of 45,955 cells revealed an unprecedented level of heterogeneity in cellular senescence. We found that cultured MSCs underwent progressive cell aging, accompanied by the gradual loss of immunosuppressive function. Moreover, compared to adult MSCs (derived from AD and the BM), perinatal MSCs (derived from the PM and UC) had fewer aging cells and exhibited more potent suppressive activity. Mechanistically, we found that the impaired immunomodulatory function of senescent MSCs was associated with reduced expression of the immunosuppressive surface molecule PD-L1, which was demonstrated to be crucial for mediating the immunosuppressive activity of MSCs. Next, we performed single-cell transcriptome analysis and revealed that T-cell hyperactivation was evident in a cohort of refractory ITP patients who had no long-lasting remission after splenectomy. We therefore conducted the registered clinical trial (NCT04014166) of the use of UC-derived MSCs for refractory ITP. In this single-center, phase I trial, six refractory ITP patients received four rounds of three different doses of UC-derived MSC transfusions (0.5 × 106 MSCs/kg, n = 3; 1.0 × 106 MSCs/kg, n = 2; 2.0 × 106 MSCs/kg, n = 1). Notably, all three participants who received 1.0 × 106 or 2.0 × 106 MSCs/kg responded to the transfusions, with a manageable safety profile, while all three participants who received 0.5 × 106 MSCs/kg had no response to the transfusions. Our findings reveal the pivotal roles of cell aging and PD-L1 expression in determining the immunosuppressive efficacy of MSCs and demonstrate that PD-L1 abundant perinatal MSCs are effective in treating refractory ITP with T cell hyperactivation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A 3-Year Follow-up Comparison of Clinical Outcomes from Zuma-5 (Axicabtagene Ciloleucel) and the International Scholar-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma (R/R FL)

Introduction: In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in r/r FL patients. When ZUMA-5 24-month data were compared to SCHOLAR-5, clinically significant benefits in overall response rate (ORR) and survival outcomes were shown in patients treated with axi-cel (ASH 2021, Palomba et al., abstract 3543). The aim of this study was to compare clinical outcomes from updated 36-month ZUMA-5 to a weighted sample from the SCHOLAR-5 cohort. Methods: The international SCHOLAR-5 external control cohort consists of r/r FL patients from 7 institutions in 5 countries who initiated a third or higher (3L+) line of therapy (LOT) after July 2014 as well as patients from the pivotal DELTA trial initiating treatment following idelalisib. ZUMA-5 trial eligibility criteria were applied to the SCHOLAR-5 cohort with patients excluded or censored upon transformation. The SCHOLAR-5 and ZUMA-5 cohorts were balanced for patient characteristics through propensity scoring on prespecified prognostic factors and standardized mortality ratio weighting. Characteristics with a standardized mean difference (SMD) <0.1 were deemed balanced. Overall survival (OS), progression-free survival (PFS) and time-to-next treatment (TTNT) were evaluated using Kaplan-Meier analysis. Results: 143 patients were identified in SCHOLAR-5, reducing to 129 patients after applying propensity score weights versus 127 patients in ZUMA-5. Median follow-up time for ZUMA-5 and SCHOLAR-5 were 36.8 and 26.2 months, respectively. Variables that were successfully balanced (SMD<0.1) included POD24, number of prior LOT, relapsed vs refractory, prior stem cell transplant, size of largest nodal mass, response to prior LOT, time since last therapy, and age. ORR was 54.0% (69/129) in SCHOLAR-5 compared to 93.7% (119/127) in ZUMA-5. CR was 45/129 (34.9%) in SCHOLAR-5 compared to 100/127 (78.7%) in ZUMA-5. The median PFS was 13.0 months in SCHOLAR-5 compared to 40.2 months in ZUMA-5 (Figure 1a). Median TTNT was 26.5 months in SCHOLAR-5 and was not reached in ZUMA-5. Median OS was not reached in SCHOLAR-5 or ZUMA-5 (Figure 1b). The hazard ratios for PFS, TTNT and OS were 0.27 (95%CI: 0.18-0.41), 0.60 (95%CI: 0.39 - 0.93), and 0.56 (95%CI: 0.33-0.95), respectively. PFS at 36 months was 6.5% (95%CI: 0.0 - 17.0) in SCHOLAR-5, compared to 54.4% (95% CI: 44.2 - 63.5) in ZUMA-5. TTNT at 36 months was 45.7% (95%CI: 33.1 - 58.3) in SCHOLAR-5, compared to 59.5% (95%CI: 50.2 - 67.6) in ZUMA-5. OS at 36 months was 64.3% (95%CI: 52.2 - 76.4) in SCHOLAR-5, compared to 75.5% (95% CI: 66.9 - 82.2) in ZUMA-5. Conclusion: After follow-up, axi-cel continues to demonstrate a substantial and statistically significant improvement in meaningful clinical endpoints including ORR, CR, PFS, TTNT and OS compared to currently available therapies for r/r FL patients, highlighting the durable treatment effect of axi-cel. These findings suggest that axi-cel addresses an important unmet medical need for r/r FL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes for Patients with Relapsed or Refractory (R/R) Aggressive B-Cell Non-Hodgkin's Lymphoma (aBNHL) Treated with Commercial Tisagenlecleucel: Subgroup Analyses from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy that provides high rates of durable response, with a manageable safety profile, in adult patients with R/R diffuse large B-cell lymphoma (DLBCL). An overall response rate (ORR) of 53% and progression-free survival (PFS) rate of 33% at 24 months were observed in the pivotal Phase II trial, JULIET (NCT02445248) [Schuster et al. Lancet Oncol 2021; Jaeger et al. Blood 2020]. CIBMTR registry data revealed similar efficacy and a more favorable safety profile for patients with aBNHL treated with tisagenlecleucel in the commercial setting [Landsburg et al.Blood 2021]. The analyses presented here feature a larger cohort with longer follow-up, with outcomes analyzed by pre-infusion clinicopathologic and treatment characteristics. Methods: This non-interventional prospective study used data from the CIBMTR registry and included adult patients with R/R aBNHL in the USA, Canada, and Israel who received commercial tisagenlecleucel after August 30, 2017. Patients were stratified by eligibility for JULIET based on characteristics reported in the registry, such as disease histology, ECOG performance status (PS), comorbidities (recorded as pulmonary, cardiac, renal, or hepatic), and disease status at infusion. Outcomes were assessed in subgroups by reason for JULIET ineligibility, and by lactate dehydrogenase (LDH) level and lymphodepleting chemotherapy (LDC) regimen. LDH was taken as the last known value prior to LDC, or prior to infusion for patients who did not receive LDC. The safety and efficacy sets comprised patients who completed Day 100 safety and efficacy forms, respectively, including those who died prior to Day 100. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Results: As of May 4, 2022, data were collected from 1159 patients who received commercial tisagenlecleucel; the median manufacturing turnaround time was 26 days (IQR 24-30). Median age was 67.1 years, 61.2% were male, and 80% had DLBCL. There were 361 JULIET-eligible patients, 641 JULIET-ineligible patients, and 157 patients whose eligibility status could not be defined due to missing data. In the efficacy set (N=968), over a median follow-up of 23.2 months (range: 3.1-46.4), the ORR was 59.5% (Table 1). Month 24 outcomes were 28.4% for PFS, 52.6% for duration of response, and 43.6% for overall survival (OS). Patients with normal versus elevated LDH had improved efficacy outcomes (Table 2), while type of LDC regimen did not appear to impact efficacy (Table 2). Considering individual reasons for JULIET ineligibility, patients in morphologic complete response (CR) at infusion had higher ORR (87.3%) and 24-month PFS (46.3%) and OS (66.1%) than JULIET-eligible patients (Table 1). In patients with ECOG PS ≥2, as well as those with comorbidities (including pulmonary, cardiac, and hepatic disease), PFS was comparable with the JULIET-eligible population (Table 1). In the safety set (N=990), grade ≥3 CRS and ICANS occurred in 6.0% and 7.4% of patients, respectively. Compared with JULIET-eligible patients, rates of CRS and ICANS were lower for patients in morphologic CR at infusion, and higher among those with ECOG PS ≥2. Rates of grade ≥3 CRS were similar between patients with comorbidities and the JULIET-eligible population (Table 1). Conclusions: These analyses using data reported to the CIBMTR, with 1159 patients and >20 months' median follow-up, confirm that real-world outcomes with tisagenlecleucel are broadly similar to those observed in JULIET. Among all patients, normal LDH pre-infusion, but not LDC regimen received, was associated with significantly improved efficacy outcomes. Patients with comorbidities that would have rendered them ineligible for JULIET had similar efficacy outcomes to JULIET-eligible patients. Additionally, efficacy outcomes were similar in patients ineligible for JULIET due to ECOG PS ≥2, albeit with higher rates of grade ≥3 CRS and ICANS. A significantly higher response rate and trend towards improved survival outcomes were observed among patients in morphologic CR before infusion. These data suggest that tisagenlecleucel is appropriate therapy for several subsets of patients who would have been ineligible for JULIET. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Single-Agent Zandelisib Administered By Intermittent Dosing in Patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Final Results of the Tidal Phase 2 Study

Introduction: Zandelisib is a novel, highly selective, structurally differentiated, oral PI3Kδ inhibitor. Its on-target residence time (≥5 hours) and high volume of distribution lead to higher tumor exposure relative to plasma over time. In a dose optimization Phase 1b study in various B-cell malignancies, zandelisib was evaluated initially by continuous dosing (CD), and then by intermittent dosing (ID) to allow regulatory T-cell repopulation, thereby reducing immune-related adverse events (AEs) (Pagel et al. Lancet Oncol 2022). The TIDAL trial (NCT03768505) started as a randomized, double-blind, 2-arm study to evaluate the safety and efficacy of zandelisib CD (n=16) vs. ID (n=121) in R/R FL and marginal zone lymphoma (MZL) patients (pts). Here we present results from the final analysis of the FL cohort in the ID arm. Methods: Eligible pts ≥18 years with FL Grade I-IIIA, ECOG performance status 0-1, progressive disease after ≥2 prior therapies including an anti-CD20 antibody and chemotherapy, and no prior PI3K inhibitor, provided consent and subsequently received zandelisib 60 mg orally once daily for two 28-day cycles, then ID (days 1-7 of 28-day cycles). The study arm evaluating zandelisib 60 mg daily CD closed early to enrollment after maturing data from the Ph 1b study showed pts on ID having fewer discontinuations due to treatment-emergent AEs and a high rate of durable responses. Study treatment was administered until disease progression or intolerance. The primary efficacy endpoint was objective response rate (ORR) as assessed by blinded independent central review (BICR) using modified Lugano Classification. Secondary endpoints were duration of response (DOR), complete response (CR) rate, median progression-free survival (mPFS), safety and tolerability. Prophylaxis for Pneumocystis jirovecii pneumonia was not mandatory in this single agent trial. Results: Between June 2019 and September 2021, 121 FL pts were enrolled in the ID arm, intent-to-treat (ITT) population, with the initial 91 pts representing the primary efficacy population (PEP). The median number of prior therapies was 3 (range 2-8), 28 pts (23.1%) had prior stem cell transplant, 54 pts (44.6%) were refractory to last therapy, 42 pts (34.7%) had bulky disease (≥5 cm), and 68 pts (56.2%) were POD24. Efficacy data overall and by subgroup (POD24, prior therapy, refractoriness) are shown in the Table. The ORR (CR rate) in the PEP and ITT were 72.5% (36.3%) and 70.2% (34.7%). With median follow-up of 11.3 months in PEP and 9.3 months in ITT, median DOR was estimated at 16.4 and 16.4 months, respectively. Preliminary PFS in the ITT population is shown in the Figure. With a median follow-up of 14.3 months (range: 1.0-30.5) among 121 pts, the most common AEs (all grade/Gr ≥3) were diarrhea (37.2%/5.8%), neutropenia (28.9%/21.5%), nausea (22.3%/0), fatigue (19.0%/0), pyrexia (19.0%/1.7%), and abdominal pain (15.7%/0.8%). 15 pts (12.4%) discontinued therapy due to treatment-related AE. Gr ≥3 AEs of special interest (AESI) in the ID arm were diarrhea in 7 pts (5.8%), lung infection/pneumonia in 6 (5.0%), noninfectious colitis in 4 (3.3%), rash in 4 (3.3 %), stomatitis in 3 (2.5%), and 1 (0.8%) each for ALT and AST increased and noninfectious pneumonitis. In 16 pts in the CD arm, 5 (31.3%) discontinued therapy due to drug-related AE, and 4 (25%) had Gr ≥3 diarrhea/colitis. Gr 5 AEs in the ID arm, excluding COVID-19, were tumor lysis syndrome (1 pt) and pneumonia (1 pt). There were 17 pts with COVID events, fatal in 5. Conclusions: Single agent zandelisib on ID was associated with high rate of durable responses (72.5% ORR, 36.3% CR rate in PEP) in heavily pretreated R/R FL pts, including those with POD24 and refractory disease, and was associated with a relatively lower incidence of Gr ≥3 AESI and AE-related discontinuations, compared with CD. Based on the safety and efficacy profiles observed in this study, these results support further evaluation of zandelisib ID, alone or in combinations, in various B-cell malignancies. Zandelisib plus rituximab vs. chemoimmunotherapy is being evaluated in the randomized phase 3 study COASTAL in R/R FL and MZL (NCT04745832). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Identification of IL-4 As a Key Regulator of CAR T-Cell Exhaustion Using Functional Genomics and Correlates of the Zuma-1 Clinical Trial

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CART19) has shown remarkable overall response rates in the treatment of hematological malignancies. However, durable response rates remain at approximately 40%. CART cell in vivo functions depend on their associated cell fate following infusion. T-cell exhaustion is an acquired and epigenetically regulated state of dysfunction that is associated with decreased proliferation and efficacy. While this phenomenon is widely considered a major limitation of CART cell therapy, mechanisms of CART cell exhaustion are poorly understood and vary depending on construct design and disease settings. Second generation CART19 cells with a CD28 costimulatory domain (CART19-28ζ) exhibit reduced persistence as compared to CART19 cells with a 4-1BB costimulatory domain. In this study, we aimed to interrogate the epigenetic landscape of exhaustion in CART19-28ζ cells. To ensure rigor, we employed the following three independent strategies: 1) RNA and ATAC sequencing on unstimulated vs. exhausted healthy donor CART19-28ζ cells by utilizing an in vitro model for exhaustion, 2) RNA and ATAC sequencing on pre-infusion axi-cel cell products from patients with B cell lymphoma treated in the pivotal Zuma-1 clinical trial that led to the FDA approval of axi-cel, comparing responders to non-responders, 3) a genome-wide CRISPR knockout screen in healthy donor CART19-28ζ cells. To begin our studies, we developed a 14-day in vitro repeated stimulation assay with healthy donor CART19-28ζ cells to model antigen-driven exhaustion. After 7 days of repeated stimulation through the CAR with the CD19+ tumor cell line, JeKo-1, CART19-28ζ cells demonstrated phenotypic and functional hallmarks of exhaustion as compared to baseline CART19-28ζ cells, as characterized by: 1) upregulated inhibitory receptors (PD-1: p <0.0001, TIM-3: p <0.0001, and LAG-3: p = 0.02), 2) decreased proliferation (p <0.0001), 3) CD4 loss (p < 0.0001), and 4) a decrease in the percent of cells with positive intracellular staining for stimulatory and effector cytokines (IL-2: p <0.0001 and TNF-α: p <0.0001). RNA sequencing identified 449 significantly upregulated genes and 320 significantly downregulated genes in exhausted CART19-28ζ cells. ATAC sequencing identified 411 gene regions with increased accessibility and 445 gene regions with decreased accessibility. Overlap of RNA and ATAC results showed 105 genes that were both differentially expressed and differentially accessible. Ingenuity pathway analysis of these genes showed activation of the T-cell exhaustion pathway (p = 0.004, Z= 1.0), a potential role for the Th1 and Th2 activation pathway (p < 0.0001) and identified IL-4 as a significant upstream regulator of exhaustion (p < 0.0001). Next, we studied the transcriptional and epigenetic signature of baseline axi-cel products by comparing responders, patients who achieved a complete remission as best response, to non-responders, patients who achieved stable or progressive disease as best response. RNA sequencing showed 54 differentially expressed genes and ATAC sequencing showed 24 differentially accessible gene regions. Only two genes, IL-4 and HLA-DQB1, were upregulated in non-responders based on both RNA and ATAC sequencing data (Figure 1A). Then, by using our in vitro exhaustion model to conduct a genome-wide CRISPR knockout screen in CART19-28ζ cells from healthy donors, we saw enrichment of genes involved in the suppression of IL-4- mediated signaling as identified by gene ontology enrichment analysis (p = 0.0001). Finally, to validate the functional impact of IL-4 on CART cells, we assessed effector functions of healthy donor CART19-28ζ cells following treatment with human recombinant IL-4. CART19-28ζ cells co-cultured with JeKo-1 in the presence of human recombinant IL-4 exhibited a reduction in antigen specific proliferation (p = 0.027), an increase in inhibitory receptor expression (TIM-3: p = 0.002 and LAG-3: p = 0.007), and a decrease in cytotoxicity as compared to vehicle treated cells (Figure 1B). IL-4 induced CART19-28ζ cell modulation was not due to a direct impact on tumor cells as identified by no change in tumor cytotoxicity or proliferation when JeKo-1 cells alone were treated with human recombinant IL-4. Together, this data suggests that the IL-4 axis may function as a key regulator of CART19 therapy failure associated with CART cell exhaustion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Measurable residual disease in hairy cell leukemia: Technical considerations and clinical significance.

Hairy cell leukemia (HCL) is a rare type of chronic lymphoid leukemia originating from a mature B lymphocyte. A diagnosis of HCL is based on cytology, confirmed by multiparametric flow cytometry (MFC) studies using anti-B-cell monoclonal antibodies, together with a panel of antibodies more specific to HCL, such as CD11c, CD25, CD103 and CD123. Recently, the BRAF V600E mutation has been described as a disease-defining genetic event. Measurable residual disease (MRD) is defined as the lowest level of HCL cells that can be detected accurately and reproducibly using validated methods; as MRD negativity is associated with high rates of durable complete response, by clearing MRD, the long-term outcome may be improved in patients with advanced HCL. MRD is typically detected using bone marrow, and in some cases, peripheral blood; however, in HCL, discrepancies frequently exist between MRD results obtained from blood, bone marrow aspirate and core biopsy. Among the methods used for MRD detection, MFC appears to be a more sensitive technique than immunohistochemistry. Molecular tests are also used, such as real-time quantitative PCR for unique immunoglobulin heavy chain (IgH) gene rearrangements and PCR techniques with clone specificity for BRAF V600E. Clone-specific PCR (spPCR) is able to detect one HCL cell in 106 normal cells, and is particularly suitable for patients found to be negative for MRD by MFC. Recently, the Hairy Cell Leukemia Consortium created a platform to work on a definition for MRD, and establish the optimal time point, tissue type and method for measuring MRD. This.

Chimeric Antigen Receptor T-cell Therapy: Imaging Response Criteria and Relation to Progression-free and Overall Survival.

Chimeric Antigen Receptor T-cell Therapy: Imaging Response Criteria and Relation to Progression-free and Overall Survival.

OA03.06 CodeBreaK 100/101: First Report of Safety/Efficacy of Sotorasib in Combination with Pembrolizumab or Atezolizumab in Advanced KRAS p.G12C NSCLC

Sotorasib monotherapy has demonstrated a durable objective response rate (ORR) of 41%, and 33% 2-year overall survival (OS) in advanced pre-treated KRAS p.G12C-mutated NSCLC. In preclinical studies, sotorasib combined with anti-PD-1 therapy increased CD8+ T-cell infiltration and enhanced anti-tumor efficacy. Here we provide the first assessment of safety and efficacy of sotorasib with either pembrolizumab (Pembro) or atezolizumab (Atezo) anti-PD-(L)1 immunotherapy (IO) from CodeBreaK 100/101 phase 1b dose exploration.

Non-viral, specifically targeted CAR-T cells achieve high safety and efficacy in B-NHL

Recently, chimeric antigen receptor (CAR)-T cell therapy has shown great promise in treating haematological malignancies1–7. However, CAR-T cell therapy currently has several limitations8–12. Here we successfully developed a two-in-one approach to generate non-viral, gene-specific targeted CAR-T cells through CRISPR–Cas9. Using the optimized protocol, we demonstrated feasibility in a preclinical study by inserting an anti-CD19 CAR cassette into the AAVS1 safe-harbour locus. Furthermore, an innovative type of anti-CD19 CAR-T cell with PD1 integration was developed and showed superior ability to eradicate tumour cells in xenograft models. In adoptive therapy for relapsed/refractory aggressive B cell non-Hodgkin lymphoma (ClinicalTrials.gov, NCT04213469), we observed a high rate (87.5%) of complete remission and durable responses without serious adverse events in eight patients. Notably, these enhanced CAR-T cells were effective even at a low infusion dose and with a low percentage of CAR+ cells. Single-cell analysis showed that the electroporation method resulted in a high percentage of memory T cells in infusion products, and PD1 interference enhanced anti-tumour immune functions, further validating the advantages of non-viral, PD1-integrated CAR-T cells. Collectively, our results demonstrate the high safety and efficacy of non-viral, gene-specific integrated CAR-T cells, thus providing an innovative technology for CAR-T cell therapy.

Teclistamab in Relapsed or Refractory Multiple Myeloma

BackgroundTeclistamab is a T-cell–redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma.MethodsIn this phase 1–2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better).ResultsAmong 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell–associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).ConclusionsTeclistamab resulted in a high rate of deep and durable response in patients with triple-class–exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.)

Axicabtagene ciloleucel for the treatment of relapsed or refractory follicular lymphoma

ABSTRACT Introduction Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was recently approved for relapsed or refractory follicular lymphoma following progression on two or more lines of therapy including an anti-CD20 monoclonal antibody with an alkylating agent, providing a therapeutic breakthrough in a subset of indolent non-Hodgkin lymphoma associated with poor clinical outcomes. Areas covered In this article, we outline the drug profile of axicabtagene ciloleucel in comparison to currently approved agents and other CAR T-cell and T-cell redirecting therapies under investigation for the treatment of relapsed or refractory follicular lymphoma. We also review the efficacy, safety, and pharmacokinetic data from the ZUMA-5 phase II trial, which forms the basis of the recent approval of axicabtagene ciloleucel. Expert opinion Axicabtagene ciloleucel is the first cellular therapy approved for relapsed or refractory follicular lymphoma, demonstrating high rates of durable responses and a manageable toxicity profile in heavily pre-treated patients.

Durable complete response rates following radiotherapy and immunotherapy combination in recurrent and metastatic head and neck squamous cell carcinoma: A retrospective single-centre cohort study.

Durable complete response rates following radiotherapy and immunotherapy combination in recurrent and metastatic head and neck squamous cell carcinoma: A retrospective single-centre cohort study.

Current State of Cell Therapies for Genitourinary Malignancies

Genitourinary (GU) cancers have greatly benefited from immunotherapy treatments, such as immune checkpoint inhibitors. However, the durable clinical response rate for these agents remains relatively low, calling for more innovative immunotherapy approaches. Adoptive cell therapy has shown a significant advancement in the treatment of cancer in recent years and represents a great potential for the treatment of GU cancers. This review summarizes the current advancements in cellular therapy strategies for the treatment of renal cell carcinoma, bladder cancer, and prostate and penile cancers. Further, current and past clinical trials of adoptive cell therapy in GU tumors are reviewed. Finally, a perspective on the future of cell therapy in GU tumors is discussed.

Abstract 6146: PD1 expression and immune-active lymphocytes can predict recurrence of hepatocellular carcinoma

Abstract Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Curative treatments in early-stage HCC are hampered by high recurrence rates, and targeted therapies against HCC are rare. Little is known about the impact of tumor microenvironment (TME) in this tumor. Manipulation of the immune system by tumors leads to compromised antigen recognition and an immunosuppressive microenvironment. One immunomodulatory strategy employed by malignant tumors is the expression of the programmed cell death receptor 1 ligand (PD-L1), whose receptor is expressed on activated T cells (PD-1). The use of immune checkpoint inhibitors (ICI) has shown antitumor activity and unprecedented rates of durable clinical responses in various cancer types. In HCC, nivolumab and pembrolizumab are described as possible second line therapies. Expression of PD-1 and PD-L1 in the TME has prognostic importance and can predict response to ICI. The aim of our study was to investigate the impact of PD-1 and PD-L1 expression on HCC recurrence and the relation to their cancer-immune phenotypes. Materials and methods: Immunohistochemical staining was performed on archival tissue from 91 HCC, primary and recurrence, using the following antibodies: NAT105 (PD-1) and Ventana SP263 (PD-L1). On the basis of protein expression, tumors were classified as immunologically active, excluded or deserted. PD-1 and PD-L1 immunoreactivity was evaluated as the proportion of positive staining of the total number of immune cells (0%, &amp;lt;1% and &amp;gt;1%). Results: Basic tumor characteristics were not related to recurrence of HCC. However, the immune-excluded subclass showed significant association with recurrence in HCC. The majority of non-recurrent HCC showed PD-1 expression &amp;gt;1% (78%; 38/49), also statistically significant. Conversely, recurrent HCC showed low PD-1 expression (0% or &amp;lt;1%) in 42% (19/45) of the cases. Of note, HCC classified as immune active were enriched for PD-1 positive (&amp;gt;1%) (77%; 49/64). An association between HCC recurrence and PD-L1 expression on tumor cells was not found. Conclusion: In concordance with previous reports, we found an association between low frequency of PD-1 expression and increased HCC recurrence, as well as the lack of impact of PD-L1 expression on HCC recurrence. Furthermore, our results suggest that HCC recurrence may be more frequent in immune-exclusive tumors. Pembrolizumab as adjuvant instead of 2nd line therapy should be further investigated. Citation Format: Gabriel Fridolin Hess, Mairene Coto-Llerena, Jasmin Zeindler, Silvio Däster, Simone Muenst, Jürg Vosbeck, Caner Ercan, Otto Kollmar, Salavtore Piscuoglio, Savas Deniz Soysal. PD1 expression and immune-active lymphocytes can predict recurrence of hepatocellular carcinoma [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 6146.

Abstract 4182: Intratumoral treatment with VAX014 facilitates in situ immunization leading to systemic antitumor responses that enhance systemic immune checkpoint blockade

Abstract Intratumorally (i.t.) delivered immunotherapies stimulate in situ immunization by promoting local tumor inflammation, immune cell recruitment, and the generation of systemic antitumor lymphocytic responses. Clinical studies indicate combining i.t. immunotherapy with systemic immune checkpoint blockade (ICB) enhances durable complete response rates (CRR) in treated and distal untreated tumors (abscopal effect), although the number of i.t. therapies tested in this setting remains is limited. The purpose of this study was to evaluate and characterize the immunotherapeutic activity of VAX014, a novel clinical-stage bacterial minicell-based oncolytic agent, following i.t. delivery in two syngeneic murine solid tumor models. The nonimmunogenic B16F10 melanoma and immunogenic MB49 urothelial carcinoma models were used to establish single agent activity of VAX014 in mice bearing a single intradermal (i.d.) tumor, followed by an evaluation of synergy between VAX014 and ICB combinations (CTLA-4 ± PD-1) in mice bearing dual bilateral i.d. B16F10 tumors where only one tumor is treated with VAX014.Weekly i.t. treatment with VAX014 led to significant CD8+ T cell mediated antitumor activity in single i.d. tumor models. A significant reduction in tumor growth rate was observed in all mice (p&amp;lt; 0.0001, 38/38 for B16F10; p&amp;lt; 0.0001, 12/12 for MB49) which ultimately resulted in a durable CRR in 58.0% and 100% in the B16F10 and MB49 models, respectively. B16F10 tumors actively responding to i.t. treatment with VAX014 had a significant increase in CD8+ T cells (p= 0.0004) with a concomitant decrease in CD11b+ myeloid cells (p= 0.039) even after a single i.t. dose of VAX014. VAX014-mediated antitumor activity was specific to the treated tumor type as determined by cytotoxic T lymphocyte assay against the treated tumor cell line versus haplotype matched control target cells (p= 0.0015). Using a bilateral variation of each model, VAX014 exhibited a significant abscopal effect in the immunogenic MB49 model (22.0% CRR and ↓ tumor growth rate in untreated tumors, p= 0.009), an effect that was less pronounced in the nonimmunogenic B16F10 model. Addition of systemic CTLA-4 ICB significantly enhanced abscopal activity in the bilateral B16F10 model whereas PD-1 ICB did not. Remarkably, tripartite combination of VAX014 with CTLA-4/PD-1 ICB resulted in a significant reduction in treated (p&amp;lt; 0.0001) and distal untreated B16F10 tumors (p&amp;lt; 0.0012) as well as an enhanced survival advantage versus CTLA-4/PD-1 ICB combination (p= 0.03). Survival was associated with an improved CRR of both tumors (50.0% vs. 20.0%).In conclusion, these preclinical data provide scientific rationale and set the foundation for i.t. treatment with VAX014 in patients with injectable tumors refractory to standard treatment options and may be particularly effective when combined with systemic ICB. Citation Format: Shingo Tsuji, Katherine A. Reil, Kinsey L. Nelson, Kathleen L. McGuire, Matthew J. Giacalone. Intratumoral treatment with VAX014 facilitates in situ immunization leading to systemic antitumor responses that enhance systemic immune checkpoint blockade [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 4182.