Combination Chemoimmunotherapy Research Articles

BTKi combined with chemical immunotherapy in the initial treatment of aggressive mantle cell lymphoma: A retrospective study.

To explore the safety and efficacy of Bruton's tyrosine kinase inhibitor (BTKi) combined with immunological therapy in untreated patients with aggressive mantle cell lymphoma. A retrospective study was conducted on 9 previously untreated patients who received BTKi combined with immunological therapy, which means using immunological therapy and BTKi at the same time. The median age of the patients was 61 years, 7 were males, and the median follow-up time was 14 months. Among the 7 evaluable patients, the median follow-up was 14 months, and the objective remission rate was 100% (complete remission rate 86%, partial remission rate 14%), while the median progression-free survival and overall survival were not achieved. No patients were dead. The progression-free survival rate of 6 patients in the low-risk group was 100%. The combination of BTKi and chemoimmunotherapy has shown excellent therapeutic results in untreated patients of aggressive mantle cell lymphoma. At the same time, it also can prolong the survival time of high-risk patients. The combined therapy has acceptable safety in previously untreated patients. Hematological toxicity is the most common side effect and infection is the second one. A rash reaction was seen occasionally. There are no heart-related adverse events in the study. There are no new adverse effects caused by the combined treatment.

Comparative efficacy of chemo-immunotherapy combination regimens in the frontline setting for NSCLC based on reconstructed patient data

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of metastatic NSCLC and have become standard first-line therapy both as monotherapy, for patients with PD-L1 expression ≥50%, and in combination with chemotherapy (CT), regardless of PD-L1 expression. This study used an artificial intelligence technique, the IPDfromKM method, to reconstruct individual patient data from Kaplan-Meier curves of phase III randomised clinical trial results to provide a comparative overview of different first-line chemo-immunotherapy options. Overall survival (OS) was estimated using hazard ratios and restricted mean survival time (RMST). Ten clinical trials were included in the analysis. In the squamous population, combinations of cemiplimab + CT (HR = 0.56), pembrolizumab + CT (HR = 0.67), and nivolumab + ipilimumab + CT (HR = 0.71) significantly improved OS compared with CT alone, with no difference between treatments. At longer follow-up, nivolumab + ipilimumab + CT showed longer RMST compared to pembrolizumab + CT in the PD-L1 < 1% subgroup (24.9 months vs. 22.8 months). In non-squamous NSCLC, the survival benefit of ICIs + CT was much more homogeneous, with similar results across the different options. Overall, pembrolizumab + CT showed the best results both in terms of HR (0.68, 95%CI 0.60-0.77) and RMST at long follow-up (30.4 months in the PDL-1 ≥ 1% subgroup and 24 months in the PDL-1 < 1% population). In conclusion, there are some differences between frontline options for treating metastatic NSCLC based on tumour histology and PD-L1 expression. However, further head-to-head trials and longer follow-up are needed to clarify the clinical impact of these differences.

Systemic anti-cancer treatment and healthcare utilization at end of life: A SEER Medicare analysis.

276 Background: Use of chemotherapy at end-of-life (EOL) is associated with adverse quality of life, higher costs, increased hospitalizations (HL), emergency department (ED), and intensive care unit (ICU) utilization and lower hospice (HP) use. While EOL chemotherapy use has declined in recent years, EOL immunotherapy use has increased. It is unknown how the trend of increased immunotherapy use at the EOL is associated with healthcare utilization. We evaluated the association between types of systemic anticancer therapy (SACT) within 30 days of death and hospitalizations, emergency department, intensive care unit, and hospice use. Methods: We identified patients in the SEER-Medicare database with a diagnosis date of 2005-2019 and death date of 2015-2020 with the following cancers: breast, colorectal, lung, prostate, bladder, cervix, kidney, leukemia, liver, lymphoma, myeloma, ovarian, pancreas, skin, and uterine. EOL SACT was defined as SACT received within 30 days of death, categorized as combination chemo-immunotherapy, immunotherapy, and chemotherapy. We analyzed associations between EOL SACT use (overall and by type), and healthcare utilization in the last 30-days of life (ED, HL, ICU, and HP) with chi-square tests and multivariable regression, controlling for sociodemographic and cancer covariates. Results: Of 499,607 beneficiaries, 37,595 (7.5%) received SACT within 30 days of death. Compared to no EOL SACT, any SACT use was associated with higher ED [75.5% vs 50.8%], HL [71.0% vs 48.7%] and ICU (35.7% vs 23.3%) and lower HP enrollment (46.1% vs 59.3%) and number of days in HP (2.4 vs 6.5 days) (all p &lt;0.001, table). After adjusting for covariates, patients with EOL SACT were more likely to have HL (odds ratio [OR], 2.43; 95% confidence interval [CI], 2.38-2.49), ED visits (OR, 2.87; 95% CI, 2.80-2.94), and ICU stay (OR, 1.66; 95% CI, 1.62-1.70), and less likely to receive HP care (OR, 0.62; 95% CI: 0.61-0.64)-compared to no SACT use; All subtypes of EOL SACT were significantly more likely to have ED, HL, and ICU use and less likely to use HP than those with No EOL SACT (p-values &lt;0.001). Conclusions: All types SACT within 30 days of death were associated increased healthcare use compared with no EOL SACT, with combination chemo-immunotherapy having the highest ED, hospitalizations and ICU use and lowest hospice enrollment and duration. Healthcare utilization. Combination Chemo-Immunotherapy(n=5,171) Immunotherapy(n = 11,397) Chemotherapy(n = 21,027) Any SACT(n = 37,595) No SACT(n = 462,012) P -value* ED Visit (%) 76.9 73.7 76.1 75.5 50.8 &lt;.001 Hospitalizations (%) 72.5 67.7 72.5 71.0 48.7 &lt;.001 ICU use (%) 40.4 32.1 36.5 35.7 23.3 &lt;.001 Hospice use (%) 38.8 50.2 45.8 46.1 59.3 &lt;.001 Number of days Hospice (Days, Mean ± standard deviation) 1.7 ± 3.0 2.7 ± 3.9 2.4 ± 3.9 2.4 ± 3.8 6.5 ± 7.8 &lt;.001 *P-values for statistical difference between each individual SACT subgroup and No SACT and Any SACT and No SACT group.

Dendritic cells pulsed with multifunctional Wilms’ tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer

BackgroundWe aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes,...

Evidence for the evolving role of neoadjuvant and perioperative immunotherapy in resectable non-small cell lung cancer.

The treatment of early-stage non-small cell lung cancer (NSCLC) is becoming increasingly complex. Standard of care management for the past decade has been adjuvant chemotherapy following curative intent resection regardless of nodal status or tumour profile. With the increased incorporation of immunotherapy in NSCLC, especially in the locally advanced, unresectable, or metastatic settings, multiple studies have sought to assess its utility in early-stage disease. While there are suboptimal responses to neoadjuvant chemotherapy alone, there is a strong rationale for the use of neoadjuvant immunotherapy in tumour downstaging, based upon the concept of enhanced T cell priming at the time of a high tumour antigen burden, and demonstrated clinically in other solid tumours, such as melanoma. In the NSCLC cancer setting, currently over 20 combinations of chemoimmunotherapy in the neoadjuvant and perioperative setting have been studied with results variable. Multiple large phase III studies have demonstrated that neoadjuvant chemoimmunotherapy combinations result in significant advances in pathological response, disease free and overall survival which has led to practice change across the world. Currently, combination immunotherapy regimens with novel agents targeting alternate immunomodulatory pathways are now being investigated. Given this, the landscape of treatment in resectable early-stage NSCLC has become increasingly complex. This review outlines the literature of neoadjuvant and perioperative immunotherapy and discusses its potential benefits and complexities and ongoing considerations into future research.

44P Chemo-immunotherapy combination of mFOLFOX6, bevacizumab and atezolizumab after first-line therapy for advanced biliary tract cancer: The COMBATBIL imCORE trial

44P Chemo-immunotherapy combination of mFOLFOX6, bevacizumab and atezolizumab after first-line therapy for advanced biliary tract cancer: The COMBATBIL imCORE trial

CYFRA 21-1 predicts efficacy of combined chemoimmunotherapy in patients with advanced non-small cell lung cancer: a prospective observational study.

Tumor markers such as serum carcinoembryonic antigen (CEA) and cytokeratin fragment 19 (CYFRA 21-1) are utilized for assessing the effectiveness of chemotherapy in non-small cell lung cancer (NSCLC) patients. Yet, it remains uncertain whether these markers can reliably forecast responses to combined chemoimmunotherapy. Our study aimed to examine the significance and effectiveness of these markers in predicting responses among NSCLC patients undergoing combined chemoimmunotherapy. This two-part observational study involved patients with NSCLC who were treated with combined chemoimmunotherapy in Japanese hospitals. An initial retrospective study of these patients, with serum CEA and CYFRA 21-1 as prognostic factors for combined chemoimmunotherapy outcomes, served as a discovery cohort. Patients in a subsequent prospective study served as a validation cohort, where we assessed the prognostic accuracy of CEA and CYFRA 21-1 cut-off points determined by the discovery cohort. In total, 121 patients treated with combined chemoimmunotherapy were included, with 44 and 77 patients in the discovery and validation cohorts, respectively. Serum CYFRA 21-1 levels >3.0 ng/mL were significantly associated with progression-free survival (PFS) in both the discovery and validation cohorts (P=0.01, P=0.04, respectively). PFS did not differ significantly by CEA levels (P=0.21). After combined chemoimmunotherapy treatment, serum CYFRA 21-1 stands out as a potentially valuable biomarker for predicting the prognosis of NSCLC.

Perioperative FLOT + immunotherapy for resectable gastric and gastroesophageal junction cancer: A systematic review and meta-analysis.

66 Background: The current standard of care for resectable gastric and GEJ cancers is perioperative chemotherapy with FLOT.Although its benefits in improving rates of pathologic complete response, increasing prospects of R0 resection, and improving survival have been proven, efforts to find novel strategies which can improve on its gains continue.The addition of an immune checkpoint inhibitor to FLOT has been a focal point of research in this field. This meta-analysis evaluated high-quality data from clinical trials to determine the efficacy of this chemoimmunotherapy combination. Methods: A systematic search of English-language articles on PubMed, Cochrane and Google scholar was done to identify randomized trials investigating the use of perioperative FLOT and immune checkpoint inhibitors in the treatment of resectable gastric and GEJ cancer. Quality of studies was assessed using the Revised Cochrane risk-of-bias tool for randomized trials. Inverse variance was the statistical method used with random effects as the analysis model in the production of the Forest plot and calculation of odds ratio at 95% CI. Results: Three RCTs (N = 1446), each with two arms, were included in the meta-analysis. The Phase II Dante Trial (N= 295)compared perioperative FLOT alone with perioperative atezolizumab + FLOT. The Phase III Keynote 585 trial(N=203) and the phase III Matterhorn trial (N=948) compared perioperative placebo + FLOT with perioperative pembrolizumab + FLOT, and perioperative Durvalumab + FLOT, respectively. Risk of bias and heterogeneity were low. Pooled results showed that in patients given perioperative FLOT + immunotherapy, there is statistically significant improvement in the rate of pathologic complete response (OR 2.60 95% CI 1.88-3.61, p &lt;0.0001). In terms of rate of R0 resection, there was no statistically significant difference between the two groups (OR 1.02 95% CI 0.75-1.38,p= 0.92). Conclusions: This analysis shows that adding immunotherapy to FLOT improves the rate of pathologic complete response, and maintains the high rate of R0 resection, in resectable gastric and GEJ cancers. Favorable results of pending survival outcomes from these trials may help re-shape the current standard of care in this field.

Erratum for the Research Article: "Elimination of established tumors with nanodisc-based combination chemoimmunotherapy" by Kuai et al.

Erratum for the Research Article: "Elimination of established tumors with nanodisc-based combination chemoimmunotherapy" by Kuai et al.

Induction chemotherapy backbone in frail patients with advanced NSCLC treated with chemotherapy plus pembrolizumab: a single institution retrospective audit of dose intensities from modified regimens.

Guidelines historically recommended mono-chemotherapy for the 1st line treatment of elderly patients with non-small cell lung cancer (NSCLC) and poor performance status (PS). Nowadays, there is no clear indication whether chemo-immunotherapy (chemo-IO) combinations can be effectively delivered in this population. We collected induction chemotherapy data in consecutive patients with advanced NSCLC treated with carboplatin-based chemotherapy regimens plus pembrolizumab, to compute the received dose intensity (RDI) from standard regimens or patient-tailored regimens modified due to age, comorbidities and PS. Comorbidities were stratified according to the comorbidity-polypharmacy score (CPS). The established cut-off of ≥85% for RDI was used to define adequate delivery. 116 pts were treated from Feb-20 to July-23, of whom 96 and 20 with non-squamous and squamous NSCLC, treated with carboplatin-pemetrexed or carboplatin-paclitaxel doublets plus pembrolizumab, respectively. The majority of patients were aged ≥ 70 years (52.6%), the median CPS was 5, with 58.6% having a CPS ≥5, whilst 47.4%, 44.8% and 7.8% had an Eastern Cooperative Oncology Group (ECOG) - PS of 0, 1 and 2, respectively. PD-L1 TPS were <1% in 31.9% and 1-49% in 65.4%. Overall, 47.4% received a priori modified regimens due to poor PS, age, or comorbidities. Among patients with non-squamous NSCLC, median received doses of carboplatin and pemetrexed were 1.37 AUC/week and 138.8 mg/m2/week, with RDIs of 86% and 75% (p < 0.01) for patients treated with standard or modified regimens, respectively. Of note, the RDI was 57.9% among patients with ECOG-PS 2. However, patients treated with modified regimens experienced similar toxicities as those treated with standard regimens, despite being older (p < 0.01), with higher PS (p < 0.01) and more comorbid (p = 0.03). Patients treated with modified regimens achieved a shorter survival (7.1 vs 13.9 months), which is comparable to IO-free historical controls. Among patients with squamous NSCLC, 90% received modified regimens upfront, with median received doses of carboplatin and paclitaxel of 1.19 AUC/week and 40 mg/m2/week, and an overall RDI of 73.5%. Although regimen modifications ensure a safe administration of chemotherapy plus pembrolizumab in frail patients, the RDI seems to be subtherapeutic, especially in those with squamous histology. Dedicated trials are needed to implement combination strategies in this population.

Co-Delivery of Tim-3 Monoclonal Antibody and Sorafenib to Enhance Chemoimmunotherapy of Liver Cancer by Using Silicon Nanosystem

In this study, mesoporous silica nanosystem (ST/SNs) was designed to co-deliver Tim-3 mAb and sorafenib (SF) for combined chemoimmunotherapy of liver cancer. The outer shell of ST/SNs is composed of Tim-3 mAb modified with metalloproteinase 2 (MMP2)-sensitive peptide, which acts as a “gating molecule” in the blood circulation to prevent drug release, and responds to Tim-3 mAb under the action of MMP2 in the tumor microenvironment Shedding enables Tim-3 mAb and SF-triggered drug release for heterotargeted cell delivery to T cells/tumor cells. In vivo tumor inhibition experiments showed that ST/SNs significantly improved tumor inhibition in tumor-bearing mice compared with sequential administration of free SF and Tim-3 mAb. At the same time, ST/SNs significantly up-regulated the expression of anti-tumor cytokines IFN-γ and IL-12 in mouse serum and the proportion of CD3+CD4+ and CD3+CD8+ cells in the tumor, showing a good immune regulation ability. In addition, at the administered dose, the blank vector exhibited low cytotoxicity and hemolysis, and no obvious hemolysis was observed. Provincial People’s Hospital. In conclusion, this study provides a promising chemoimmunotherapy combination drug combination for clinical liver cancer treatment, and provides a potential drug carrier for chemoimmunotherapy combination therapy.

Intratumoral Escherichia Is Associated With Improved Survival to Single-Agent Immune Checkpoint Inhibition in Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSEThe impact of the intratumoral microbiome on immune checkpoint inhibitor (ICI) efficacy in patients with non-small-cell lung cancer (NSCLC) is unknown. Preclinically, intratumoral Escherichia is associated with a proinflammatory tumor microenvironment and decreased metastases. We sought to determine whether intratumoral Escherichia is associated with outcome to ICI in patients with NSCLC.PATIENTS AND METHODSWe examined the intratumoral microbiome in 958 patients with advanced NSCLC treated with ICI by querying unmapped next-generation sequencing reads against a bacterial genome database. Putative environmental contaminants were filtered using no-template controls (n = 2,378). The impact of intratumoral Escherichia detection on overall survival (OS) was assessed using univariable and multivariable analyses. The findings were further validated in an external independent cohort of 772 patients. Escherichia fluorescence in situ hybridization (FISH) and transcriptomic profiling were performed.RESULTSIn the discovery cohort, read mapping to intratumoral Escherichia was associated with significantly longer OS (16 v 11 months; hazard ratio, 0.73 [95% CI, 0.59 to 0.92]; P = .0065) in patients treated with single-agent ICI, but not combination chemoimmunotherapy. The association with OS in the single-agent ICI cohort remained statistically significant in multivariable analysis adjusting for prognostic features including PD-L1 expression (P = .023). Analysis of an external validation cohort confirmed the association with improved OS in univariable and multivariable analyses of patients treated with single-agent ICI, and not in patients treated with chemoimmunotherapy. Escherichia localization within tumor cells was supported by coregistration of FISH staining and serial hematoxylin and eosin sections. Transcriptomic analysis correlated Escherichia-positive samples with expression signatures of immune cell infiltration.CONCLUSIONRead mapping to potential intratumoral Escherichia was associated with survival to single-agent ICI in two independent cohorts of patients with NSCLC.

Timing of Palliative Care Consultation Impacts End of Life Care Outcomes in Metastatic Non-Small Cell Lung Cancer

ContextEarly specialist palliative care (PC) involvement in metastatic non-small cell lung cancer (mNSCLC) is associated with improved quality of life, less aggressive end of life (EoL) care, and longer survival. As treatment paradigms for NSCLC have evolved, PC utilization remains low. ObjectivesThis work examines how the timing and extent of PC involvement impacts outcomes and the patient experience in mNSCLC in the era of immunotherapy. MethodsThis retrospective review analyzed patients with mNSCLC who initiated first-line treatment with chemotherapy, immunotherapy, or combined chemoimmunotherapy at Duke University between March 2015 and July 2019. PC consultation and outcomes data were abstracted through November 2022. EoL care variables were analyzed using descriptive statistics. Results152 patients were stratified based on whether PC was consulted during their disease course. 80 patients (53%) never saw PC, while the 72 patients (47%) who saw PC were further stratified by time to first PC encounter and total number of PC visits. 31% were seen within two months of diagnosis (early), 33% between two and six months (intermediate), and 36% after 6 months (late). Patients who received early PC had longer median time on hospice (35 days), had lower rates of aggressive EoL care (43%), and experienced less frequent in-hospital death (14%) compared to other groups. ConclusionThis real-world study reveals that referrals to PC still occur late or not at all in mNSCLC despite demonstrated benefits of early PC integration. Early outpatient PC referrals resulted in longer time on hospice, lower frequency of aggressive EoL care, and lower rates of in-hospital death.

Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.

Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC. In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo. Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses. RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.

Systemic anti-cancer therapy and cost at end of life: A SEER Medicare analysis.

11092 Background: Systemic anticancer therapy (SACT) administered near the end of life (EOL) is associated with higher costs, driven by pharmaceuticals and associated acute care use that occurs when patients continue treatment in lieu of transition to hospice. Since 2015 overall rates of systemic therapy at the EOL have remained stable, while some chemotherapy has been replaced by costly immunotherapy. It is not known whether immunotherapy is associated with the same impact on total cost of care (TCOC) as chemotherapy. We evaluated the relationship between type of SACT vs no SACT within 30 days of death on categories of cost. Methods: We identified patients from the SEER-Medicare database diagnosed between 2005 and 2019 with solid tumors (ST) and liquid tumors (LT) who died from 2015-2020. We assessed differences in Medicare cost within 30 days of death by subtype of SACT: combination chemo-immunotherapy (CI), immunotherapy only (IO), chemotherapy only (CO) and no SACT. Dependent variables were TCOC (including all Medicare claims), as well as cost of drugs, hospitalizations, emergency department (ED), and hospice normalized and adjusted for inflation. Results: 6.2% (27,317/440,349) of ST decedents and 12.7% (7,544/59,449) LT decedents received SACT at EOL. See table. Among ST patients who received SACT, the mean TCOC was $26,282 (standard deviation (SD) $26,700) and was highest among patients receiving CI, $27,973 (SD: $26,285) vs. $17,642 (SD: $29,798) for patients without SACT ( p &lt;.001). Among LT patients who received SACT, the mean TCOC was $26,282 (SD $26,700) and was highest among CI patients $33,632 (SD: $26,283) vs. $24,689 (SD: $39,735) for patients with no SACT ( p&lt;.001). We observed higher cost for drugs, hospitalizations (except for LT patients receiving CI vs. no SACT), ED and lower hospice costs for patients receiving each SACT subgroup compared with no SACT. All results except those noted in table were significant (p &lt;.001). Conclusions: Receipt of SACT within 30 days of death was associated with significantly higher Medicare costs. Higher TCOC in those who received SACT is only partially explained by drug costs; most acute care costs were also significantly higher among patients who received any type of SACT including CI, IO, CO than among those who did not. [Table: see text]

Preliminary experience of ex-vivo expanded allogeneic universal donor TGFβi NK cell infusions in combination with irinotecan, temozolomide, and dinutuximab in patients with relapsed or refractory neuroblastoma: The Allo - STING trial.

10005 Background: Neuroblastoma (NBL) is the most common extra-cranial solid tumor in children and outcomes for children with relapsed/refractory (RR) NBL remain dismal. While the combination of chemoimmunotherapy (CIT) with the anti-GD2 antibody dinutuximab as per COG protocol ANBL1221 has improved responses, this regimen is still not curative. Dinutuximab can recruit NK cells for anticancer activity, however, NK cells are depleted in NBL patients undergoing chemotherapy. We devised a method to expand allogeneic NK cells ex vivo to improve effector function and render the NK cells resistant to TGFβ-induced suppression (TGFβi). These TGFβi NK cells are expanded from a universal donor (UD) pool, enabling multiple cycles of “off-the-shelf” high-dose therapy. We hypothesize that adoptive transfer of UD-TGFβi NK cells to patients with RR NBL sequentially following CIT is safe and improves outcomes compared to CIT alone. Methods: This Phase I/II study evaluates the safety and tolerability of UD-TGFβi NK cells in combination with CIT and compares anti-cancer efficacy to CIT alone. Eligibility includes age &lt; 30 years, RR or progressive NBL, and prior treatment with at least 4 cycles of induction chemotherapy. The treatment protocol consists of 21-day cycles of CIT as per COG protocol ANBL1221 with UD-TGFβi NK cells (1x108 cells/kg) infused on day 8. Up to six cycles of treatment are permitted. Overall response rates are defined using the Revised International NBL Response Criteria, with 95% confidence intervals compared to the results from ANBL1221. Progression-free and overall survival will be estimated by the Kaplan Meier method. Results: Four subjects (7 – 11 years) have been enrolled. All patients presented with high risk NBL: three with relapsed disease and one with refractory disease. All received at least one prior salvage therapy. Three patients have completed all 6 cycles of protocol therapy, and one remains on treatment. 20 NK cell infusions have been administered to date. All NK cell infusions occurred within the protocol specified window. One subject experienced grade 1 fever with two NK cell infusions. There have been no other adverse events attributable to the NK cells. Adverse events attributable to CIT were similar to those described in COG ANBL 1221. Treatment delays for cytopenias due to CIT occurred in two patients. Three patients achieved a partial response. A fourth patient attained prolonged stable disease (9 months) but experienced a skeletal recurrence. Conclusions: UD allo-TGFβi NK cells can be safely and feasibly administered to children with RR NBL after treatment with CIT, with early objective responses observed in the preliminary cohort of patients. Ongoing studies will assess markers of response, NK cell persistence, pharmacokinetics and pharmacodynamics. Clinical trial information: NCT04211675 .

Effect of indoximod-based chemo-immunotherapy in patients with pediatric brain tumors on activation and clonal proliferation of a circulating population of early non-exhausted stem-like CD8+ T cells whose on-treatment expansion is predictive of long-term outcome.

2566 Background: Combination chemo-immunotherapy is a promising strategy, but it is difficult to determine whether clinical responses are associated with on-target immune activation or just due to chemotherapy. The field lacks well-accepted readouts of on-treatment T cell activation/expansion to answer this question. Methods: We analyzed longitudinal blood samples from 30 patients with pediatric brain tumors treated with the IDO-inhibitor drug indoximod combined with either chemotherapy (n=27, NCT02502708, NCT04049669) or chemotherapy plus ibrutinib (n=3, NCT05106296). Patients in this “Training Set” were selected to include multiple trials, various histologies/molecular risk factors, and a range of outcomes (overall survival (OS) range 6-55 months). Longitudinal blood samples (2-11 samples/patient) were obtained over 4-36 months, depending on duration of treatment, and analyzed by single-cell RNA and TCR sequencing (scRNAseq/TCRseq). TCR clonotypes of interest were defined as having at least 2-fold expansion (or appearance de novo) during treatment compared to baseline. To calculate a “Clonal Expansion Index” (CEI), the total number of T cells belonging to treatment-expanded clonotypes was summed for each sample and expressed as a percentage of total T cells. The peak CEI value for each patient was used to stratify subjects into “Immune Responders” vs “Non-responders”, based on an optimized cutoff established by Receiver Operating Characteristic (ROC) analysis with Youden’s J statistic. Results: In these patients, CEI ranged from &lt;1% to &gt;60% of all circulating T cells. The optimized cut-point was found to be a CEI of 8.6%, producing a sensitivity of 91% and specificity of 77% for this dataset. Kaplan-Meier analysis showed a highly significant 3-fold difference in median OS for the CEI-High patients (26.5 months) compared to CEI-Low (8.9 months, p=0.0003). The CEI metric was far superior as a predictor of long-term outcome than radiographic response by RANO, RAPNO or iRANO criteria, which were not predictive. UMAP clustering and Monocle trajectory analysis of the treatment-expanded T cells revealed that the majority arose from a population of early stem-like cells (TCF7+ LEF1+ FOXP1+), progressing through a more activated stem-like population (HOBIT/ZNF683+) to attain proliferation and effector maturation states. Throughout this sequence, the T cells showed minimal markers of exhaustion (PDCD1, HAVCR2, TOX) and acquired a lytic effector phenotype. Conclusions: We hypothesize that clonal expansion of this population of non-exhausted stem-like T cells, as quantitated by the CEI assay, provides a mechanistically based pharmacodynamic readout of T cell response to indoximod-based (and perhaps other) chemo-immunotherapy.

Impact of immune-related adverse events (irAE) onset on disease response and survival in patients (pts) with head-neck cancer treated with immune check point inhibitors (ICI).

6028 Background: ICI or combination chemo-immunotherapy are the mainstay of therapy for metastatic head-neck squamous cell carcinoma (mHNSCC) due to durable responses in certain pts. irAEs have emerged as a new challenge in the management of these pts. Some studies suggest a positive correlation between irAE onset and ICI efficacy in other cancers, however, whether such an association exists in HNSCC remains incompletely explored. Methods: We performed a retrospective, single-center cohort study of pts ≥ 18 years of age, with histologically confirmed mHNSCC who received ≥ 1 dose of ICIs at the University of Virginia Comprehensive Cancer Center, VA, USA between 2013-2022. Demographics, disease and treatment characteristics, and clinical outcomes related to irAEs and ICI re-challenge were analyzed. IrAEs were graded using CTCAE v4.0 criteria by chart review. Independent sample t-tests and chi-square analyses were used for univariate comparisons. Median PFS and OS from ICI therapy initiation were estimated using Kaplan-Meier methodology and censored at date of last follow up. P-values &lt;0.05 were considered statistically significant. Results: Of 1979 pts who received ICI, 110 had mHNSCC (72.7% male; 84.5% White) with a median age of 62.4 years. ICI type included pembrolizumab or nivolumab in 109 pts, and nivolumab/ipilimumab in one pt. 53 (48%) pts experienced any grade irAE and 12 pts (11%) experienced &gt;1 irAE. The most common irAEs were hypothyroidism (30.4%), dermatitis (14.3%), and hepatitis (10.7%). CTCAE ≥G3 irAEs were seen in 22.6% pts (n=12). These included hepatitis (n=3), colitis (n=3), hypothyroidism (n=1), arthritis (n=1), pneumonitis (n=1), adrenal insufficiency (n=1), vasculitis (n=1), and cardiomyopathy (n=1). Men (62% vs 37%, p= 0.015) and pts with prior radiation therapy (83% vs 17%, p=0.047) were more likely to experience irAEs. Treatment interruption/discontinuation occurred in 43% pts with irAEs. Topical/supportive therapy was required in 52.8%, and 35.8% required systemic corticosteroids, with more than half experiencing complete irAE resolution. A statistically significant association was observed between irAE onset and objective response rate (68% vs 39%, p= 0.009). 12 pts underwent ICI re-challenge, resulting in partial response in 3 (25%), stable disease in 4 (33.3%) and progressive disease in 3 (25%) pts. There was no statistically significant difference in PFS (4.9 vs 9.7 months, p = 0.731) or OS (30.5 vs 21 months, p = 0.159) in irAE vs non-irAE groups, respectively. Conclusions: irAEs onset was associated with improved best response to ICI therapy in mHNSCC. Although OS was numerically superior in the irAE group, it did not meet statistical significance. ICI re-challenge is feasible in select pts, however further studies are needed to evaluate long term benefit of ICI re-challenge.

Clinical and translational results from REVOLUTION cohorts A (nivolumab + ipilimumab + chemotherapy) and B (hydroxychloroquine + ipilimumab + chemotherapy) in patients with previously untreated metastatic pancreatic adenocarcinoma.

4137 Background: Metastatic pancreatic adenocarcinoma (mPDAC) is largely refractory to treatment, including immunotherapy. However, recent developments in chemoimmunotherapy combinations show promise. Herein, we report results from the first 2 cohorts of REVOLUTION, an ongoing, adaptive platform study designed to assess the safety and antitumor activity of novel chemoimmunotherapy combinations in patients (pts) with untreated mPDAC. Methods: REVOLUTION (NCT04787991) is an open-label, non-randomized, exploratory platform trial. Pts were assigned by investigator choice to one of the enrolling cohorts. All pts in Cohorts A and B received 1000 mg/m2 gemcitabine, 125 mg/m2 nab-paclitaxel, and 2 doses of 1 mg/kg ipilimumab. In addition, pts received 360 mg nivolumab Q3W in Cohort A or 600 mg hydroxychloroquine BID in Cohort B. Primary endpoint: safety. Secondary endpoints: ORR, DCR, DOR, PFS, and OS. Exploratory endpoints: pharmacodynamics and association of tumor and blood biomarkers with clinical activity. Each cohort utilized a Simon two-stage design: n=15 in Stage 1 with expansion to Stage 2 (an additional n=15) based on the totality of safety, efficacy and biomarker analyses. Results: Both cohorts enrolled 15 pts each. Median treatment duration was 6.5 and 5.6 months (mo), and median study duration was 19.1 and 12.7 mo for A and B, respectively. All pts experienced a treatment-related adverse event (TRAE). Grade 3-4 TRAEs occurred in 60% of A (most common: decreased neutrophil count [n=4]) and 53% of B (most common: anemia [n=5], decreased neutrophil count [n=4]). In B, 2 pts discontinued due to AEs, with none occurring in A. One grade 5 TRAE (multiple organ dysfunction syndrome, deemed related to chemotherapy) occurred in B; none in A. Table shows efficacy results. Cohort A revealed increased activated/proliferating CD4 T cells, CD8 T cells, Tregs, and soluble PD-1 in circulation. Cohort B showed increases in activated/proliferating CD4 T cells and signs of autophagy inhibition. Preliminary multi-omic analyses that aim to associate biomarkers with clinical response will be presented. Conclusions: REVOLUTION cohorts A and B demonstrated antitumor activity in pts with mPDAC. Cohort B treatment, which included hydroxychloroquine, incurred more early discontinuations. As designed, neither cohort will advance to Stage 2, highlighting the need for further tailored therapeutic approaches in mPDAC. Clinical trial information: NCT04787991 . [Table: see text]

Impact of maintenance pemetrexed cessation on clinical outcomes of patients with metastatic non-squamous NSCLC.

8568 Background: Combination chemoimmunotherapy including pemetrexed and a PD(L)1 inhibitor is a common first line systemic approach for patients with metastatic non-squamous non-small cell lung cancer (NSCLC). Patients often discontinue maintenance pemetrexed due to adverse effects, and little is known about the impact of maintenance pemetrexed cessation on progression free survival (PFS) and overall survival (OS). Methods: 121 patients with stage IV or recurrent, metastatic non-squamous NSCLC treated at VUMC were included in this retrospective analysis. Patients diagnosed between 7/2017- 9/2023 were included if they received maintenance pemetrexed and pembrolizumab. Patients were divided into two groups: those who stopped pemetrexed due to toxicity and those who did not. PFS and OS were measured from time of stage IV or metastatic diagnosis to the date of radiographic progression or death, respectively, and compared with the Kaplan Meier method. Results: Among patients with stage IV or recurrent, metastatic NSCLC (n = 121), who remained on maintenance pemetrexed and pembrolizumab (n=68), the median PFS was 11.7 months (95% CI, 7.47-NA) compared to 24.3 months (95% CI, 19.4-NA) among patients who stopped maintenance pemetrexed (n=53; p=0.1). The median OS in the same patient groups was 25.8 months (95% CI, 13.8-NA) compared to 36.4 months (95% CI, 26.9-NA) (p=0.15), respectively. Among patients with stage IV disease at diagnosis (n = 97), the median PFS among patients who did not stop pemetrexed was 8.7 months (95% CI, 7.2–NA) compared to 24.3 months (95% CI, 17.3-NA) for patients who stopped pemetrexed (p=0.089). The median OS in these groups were 21 months (95% CI, 13.6-NA) and 38.6 months (95%, 28.0-NA) (p=0.054), respectively. Conclusions: In this study of patients with metastatic non-squamous NSCLC who received maintenance pemetrexed and pembrolizumab, patients who stopped pemetrexed due to toxicity experienced similar outcomes to those who continued with pemetrexed. The necessity of continuation of maintenance chemotherapy should be further evaluated in the immunotherapy era. [Table: see text]