Chemoimmunotherapy Of Cancer Research Articles

Inhibiting Endothelial Cell-Mediated T Lymphocyte Apoptosis with Integrin-Targeting Peptide-Drug Conjugate Filaments for Chemoimmunotherapy of Triple-Negative Breast Cancer.

Tumor-associated endothelial cells (TECs) limit antitumor immunity via inducing apoptosis of infiltrating T lymphocytes through a Fas ligand (FasL) mediated mechanism. Herein, this work creates a peptide-drug conjugate (PDC) by linking 7-ethyl-10-hydroxycamptothecin (SN38) to hydrophilic segments with either RGDR or HKD motif at their C-terminus through a glutathione-responsive linker. The PDCs spontaneously assemble into filaments in aqueous solution. The PDC filaments containing 1% of SN38-RGDR (SN38-HKD/RGDR) effectively target triple-negative breast cancer (TNBC) cells and TECs with upregulated expression of integrin, and induce immunogenic cell death (ICD) of tumor cells and FasL downregulation of TECs. SN38-HKD/RGDR increases infiltration, activity, and viability of CD8+ T cells, and thus inhibits the growth of primary tumors and pulmonary metastasis. This study highlights the synergistic modulation of cancerous cells and TECs with integrin-targeting PDC filaments as a promising strategy for TNBC chemoimmunotherapy.

Harnessing Nanomedicine to Potentiate the Chemo-Immunotherapeutic Effects of Doxorubicin and Alendronate Co-Encapsulated in Pegylated Liposomes.

Encapsulation of Doxorubicin (Dox), a potent cytotoxic agent and immunogenic cell death inducer, in pegylated (Stealth) liposomes, is well known to have major pharmacologic advantages over treatment with free Dox. Reformulation of alendronate (Ald), a potent amino-bisphosphonate, by encapsulation in pegylated liposomes, results in significant immune modulatory effects through interaction with tumor-associated macrophages and activation of a subset of gamma-delta T lymphocytes. We present here recent findings of our research work with a formulation of Dox and Ald co-encapsulated in pegylated liposomes (PLAD) and discuss its pharmacological properties vis-à-vis free Dox and the current clinical formulation of pegylated liposomal Dox. PLAD is a robust formulation with high and reproducible remote loading of Dox and high stability in plasma. Results of biodistribution studies, imaging with radionuclide-labeled liposomes, and therapeutic studies as a single agent and in combination with immune checkpoint inhibitors or gamma-delta T lymphocytes suggest that PLAD is a unique product with distinct tumor microenvironmental interactions and distinct pharmacologic properties when compared with free Dox and the clinical formulation of pegylated liposomal Dox. These results underscore the potential added value of PLAD for chemo-immunotherapy of cancer and the relevance of the co-encapsulation approach in nanomedicine.

Enhanced chemoimmunotherapy of breast cancer in mice by apolipoprotein A1-modified doxorubicin liposomes combined with interleukin-21

Backgroud: Breast cancer is a prevalent malignancy among women, with triple-negative breast cancer (TNBC) comprising approximately 15–20% of all cases, possessing high invasiveness, drug resistance and poor prognosis. Chemotherapy, the main treatment for TNBC, is limited by toxicity and drug resistance. Apolipoprotein A1 modified doxorubicin liposome (ApoA1-lip/Dox) was constructed in our previous study, with promising anti-tumour effect and improved safety been proved. However, during long-term administration, the problem of cumulative toxicity and insufficient tumour inhibition is still inevitable. Interleukin-21 is a small molecule protein secreted by T cells with various immune regulatory functions. IL-21 has significantly curative effects in numerous solid tumours, but it has the disadvantages of low response rate and short half-life. The combination of chemotherapy and immunotherapy has received increasing attention. Purpose: In this study, ApoA1 drug loading system and long-acting IL-21 are innovatively combined for tumour treatment. Methods: We combined ApoA1-lip/Dox and IL-21 for treatment and evaluated their impact on tumor-infiltrating lymphocytes and CD8+ T and NK cell cytotoxicity. Results: Combined administration significantly improved the tumour-infiltrating lymphocytes and enhanced the cytotoxicity of CD8+ T and NK cells. The combination of ApoA1-lip/Dox and IL-21 exhibits significantly enhanced anti-tumour efficacy with lower toxicity of ApoA1-lip/Dox, providing a new strategy for TNBC treatment with enhanced anti-tumour response and reduced toxicity.

Drug-induced interstitial lung disease after chemoimmunotherapy for extensive-stage small cell lung cancer

ObjectivesThe combination of chemotherapy and immune checkpoint inhibitors (chemo-ICI) has become the new standard of treatment for extensive-stage small cell lung cancer (ES-SCLC). Recently, slight changes in interstitial shadows, defined as interstitial lung abnormalities (ILA), have been identified. In patients with ES-SCLC who received chemo-ICI, there are limited data on the incidence of drug-induced interstitial lung disease (D-ILD) in daily practice and the association between the development of D-ILD and ILA in the baseline computed tomography (CT). Materials and methodsA multicenter, retrospective study was conducted to investigate the incidence of D-ILD, the risk factors for developing D-ILD, progression-free survival (PFS), and overall survival (OS) in patients with ES-SCLC who received chemo-ICI between August 2019 and November 2021. ResultsThis study enrolled 70 patients (median age, 71 years; including 58 men) from nine institutions in Japan. There were 62 patients (89%) treated with carboplatin/etoposide/atezolizumab and 8 patients treated with carboplatin or cisplatin/etoposide/durvalumab. Twenty-nine patients (41.4%) were found to have ILA at baseline CT. Eleven patients (15.7%) developed D-ILD. The proportion of patients with ILA was significantly higher in the group who developed D-ILD than in the group who did not (9/11 (81.8%) vs. 20/59 (33.9%), respectively, P = 0.0057). In addition, the frequency of ground glass attenuation (GGA) and reticulation was higher in patients who developed D-ILD. There was no significant difference in PFS and OS between patients who developed D-ILD and those who did not (median PFS, 8.0 (95% confidence interval (CI), 5.5–9.5) months vs. 5.0 (95% CI, 4.5–5.6) months, respectively, P = 0.11 and median OS, not reached (NR) (95% CI, 8.7–NR) vs. 18.2 (95% CI, 13.2–NR) months, respectively, P = 0.20). ConclusionThe incidence of D-ILD in patients with ES-SCLC who received chemo-ICI in clinical practice was higher than that in clinical trials. Patients with pre-existing ILA were more likely to develop D-ILD.

A Biomimetic Nanogel System Restores Macrophage Phagocytosis for Magnetic Resonance Imaging-Guided Synergistic Chemoimmunotherapy of Breast Cancer.

Novel strategies to facilitate tumor-specific drug delivery and restore immune attacks remain to be developed to overcome the current limitations of chemotherapy. Herein, a cancer cell membrane (CM)-camouflaged and ultrasmall iron oxide nanoparticles (USIO NPs)-loaded polyethylenimine nanogel (NG) system is reported to co-deliver docetaxel (DTX) and CD47 siRNA (siCD47). The prepared co-delivery system exhibits good colloidal stability, biocompatibility, and r1 relaxivity (1.35 mM-1 s-1 ) and enables redox-responsive release of the loaded DTX in the tumor microenvironment. The NG system realizes homologous targeting delivery of DTX and siCD47 to murine breast cancer cells (4T1 cells) for efficient chemotherapy and gene silencing; thus, inducing immunogenic cell death (ICD) and restoring macrophage phagocytic effect through downregulation of "don't eat me" signals on cancer cells. Likewise, the co-delivery system can also act on macrophages to promote their M1 polarization, which can be combined with DTX-mediated ICD and antibody-mediated immune checkpoint blockade to generate effector T cells for robust chemoimmunotherapy. Further, the USIO NPs-incorporated NG system also allows for magnetic resonance imaging of tumors. The developed biomimetic NG system acting on both cancer cells and macrophages holds a promising potential for macrophage phagocytosis-restored chemoimmunotherapy.

My Experience in a Clinical Trial for a Rare Gynecologic Cancer

In this Patient Platform, historian Susan Wade, Ph.D., shares her experience as a participant in an ongoing single-arm phase 2 study of chemoimmunotherapy and radiation for vulvar cancer. She offers her perspective on some of the challenges of having a rare tumor and participating in a clinical trial.

Redox-Responsive Dendrimer Nanogels Enable Ultrasound-Enhanced Chemoimmunotherapy of Pancreatic Cancer via Endoplasmic Reticulum Stress Amplification and Macrophage Polarization.

Developing a multifunctional nanoplatform to achieve efficient theranostics of tumors through multi-pronged strategies remains to be challenging. Here, the design of the intelligent redox-responsive generation 3 (G3) poly(amidoamine) dendrimer nanogels (NGs) loaded with gold nanoparticles (Au NPs) and chemotherapeutic drug toyocamycin (Au/Toy@G3 NGs) for ultrasound-enhanced cancer theranostics is showcased. The constructed hybrid NGs with a size of 193nm possess good colloidal stability under physiological conditions, and can be dissociated to release Au NPs and Toy in the reductive glutathione-rich tumor microenvironment (TME). The released Toy can promote the apoptosis of cancer cells through endoplasmic reticulum stress amplification and cause immunogenic cell death to maturate dendritic cells. The loaded Au NPs can induce the conversion of tumor-associated macrophages from M2-type to antitumor M1-type to remodulate the immunosuppressive TME. Combined with antibody-mediated immune checkpoint blockade, effective chemoimmunotherapy of a pancreatic tumor mouse model can be realized, and the chemoimmunotherapy effect can be further ultrasound enhanced due to the sonoporation-improved tumor permeability of NGs. The developed Au/Toy@G3 NGs also enable Au-mediated computed tomography imaging of tumors. The constructed responsive dendrimeric NGs tackle tumors through a multi-pronged chemoimmunotherapy strategy targeting both cancer cells and immune cells, which hold a promising potential for clinical translations.

Does the number of cycles of neoadjuvant therapy affect the efficacy of neoadjuvant chemoimmunotherapy for non-small cell lung cancer in locally advanced stage? Retrospective experience based on a single center.

The number of cycles of neoadjuvant therapy programmed cell death 1 (PD-1) inhibitor for locally advanced non-small cell lung cancer (NSCLC) remains controversial. From October 2019 to March 2022, neoadjuvant chemoimmunotherapy followed by radical surgery for NSCLC patients with stage II-III were retrospectively reviewed in Shanghai Pulmonary Hospital. The radiologic response was assessed according to the Response Evaluation Criteria for Solid Tumors version 1.1. The major pathological response was defined as no more than 10% residual tumor. Student'st-test, chi-square test, and Mann-Whitney test were used for univariate analysis, logistic regression analysis was used for multivariate analysis. All statistical analyses were calculated by SPSS software (version 26). Among 108 patients, the number of patients who received 2-cycle (2-cycle group) and more than 2-cycle (>2-cycle group) neoadjuvant chemoimmunotherapy were 75 (69.4%) and 33 (30.6%), respectively. Compared with patients inthe >2-cycle group, patients in the 2-cycle group had significantly smaller diagnostic radiological tumor size (37.0mm vs. 49.6mm, p=0.022) and radiological tumor regression rate (36%vs. 49%, p=0.007). However, no significant difference in pathological tumor regression rate was observed between patients in the 2-cycle group and>2-cycle group. Further logistic regression analysis demonstrated that the neoadjuvant chemoimmunotherapy cycle could independently affect the radiographic response (odds ratio [OR]: 0.173, 95% confidence interval [CI]: 0.051-0.584, p=0.005) but not for pathological response (OR: 0.450, 95% CI: 0.161-1.257, p=0.127). For patients diagnosed with stage II-III NSCLC, the number of neoadjuvant cycles administered can significantly influence the radiographic efficacy of chemoimmunotherapy.

Core-shell tecto dendrimer-mediated cooperative chemoimmunotherapy of breast cancer.

Development of effective nanomedicines to deal with tumor immunogenicity and immunosuppression is vital to improve the immunotherapy efficacy. Herein, we developed a programmed strategy not only to activate the tumoral immune microenvironment through immunogenic cell death (ICD) effect but also to promote the maturation of dendritic cells (DCs) in lymph nodes through two modules of core-shell tecto dendrimer (CSTD)-based nanomedicines. The CSTDs with amplified tumor enhanced permeability and retention effect and improved gene delivery efficiency were formed by supramolecular self-assembly of generation 5 (G5) poly(amidoamine) dendrimers as cores and G3 dendrimers as shells. One module was employed to load doxorubicin for cancer cell chemotherapy to generate ICD, while the other module with partial surface modification of zwitterions and mannose was used for serum-enhanced YTHDF1 siRNA delivery to DCs to stimulate their maturation. These two modular CSTD-based nanomedicine formulations enable enhanced chemoimmunotherapy of an orthotopic breast tumor model through programmed treatment of cancer cells and DCs, and synergistic modulation of the maturation of DCs to activate the CD8+/CD4+ T cells for tumor killing. The developed CSTD-enabled nanomodules with improved drug/gene delivery performance may be applicable to tackle other cancer types via collaborative chemoimmunotherapy.

The PRIME-CUT study: A single-arm phase 2 study of ADT with PD-1 blockade and docetaxel in men with metastatic hormone-sensitive prostate cancer.

e17089 Background: Overall survival of patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) is improved with androgen deprivation therapy (ADT) and treatment intensification. Initially, ADT induces a robust and functional immune infiltrate into the tumor microenvironment (TME), with upregulation of immune checkpoint molecules. These effects diminish as castration-resistant prostate cancer (CRPC) invariably develops. We report the first results of the phase 2 PRIME-CUT study (modulating the PRostate cancer Immune MicroEnvironment with ChemoimmUnoTherapy for metastatic prostate cancer). Methods: Eligible pts had newly diagnosed mHSPC, ECOG performance status (PS) 0 or 1, serum testosterone levels > 150 ng/dL, agreed to undergo serial metastatic tumor biopsies, and had not received ADT in the prior 6 months. Treatment consisted of ADT (degarelix 240 mg subcutaneously (SC) for one dose, followed by leuprolide 22.5 mg SC every 12 weeks) followed by anti-PD-1 antibody (cemiplimab 350 mg IV every 3 weeks) beginning four weeks after ADT initiation. With the intent of immune priming, a two-cycle lead-in of anti-PD-1 therapy was administered prior to standard of care docetaxel (75 mg/m2 every 3 weeks for six cycles). Participants received ADT and cemiplimab until study completion (52 weeks) or until a lack of clinical benefit or intolerable side effects. The primary endpoint was the rate of undetectable PSA at 6 months after chemotherapy initiation (week 37) and compared to the historical rate from the phase III CHAARTED trial (32%). Subjects were monitored for toxicity using a Bayesian adaptive study design with an early stopping rule for toxicity. Results: The study completed accrual of 20 pts (median age 62 years) from Columbia University Irving Medical Center in Aug 17, 2022. Among them, 7 self-identified race as Black and 12 self-identified their ethnicity as Hispanic. Baseline PSA ranged from 8.15 to > 5000 ng/dL (median 2513.1 ng/dL). Site of metastatic disease included: 17/20 bone, 12/20 lymph nodes, 11/20 visceral organs. Overall, 14 of 20 patients received at least 4 cycles of docetaxel. Of the 12 patients that were still on-study at 37 weeks, 2 had an undetectable PSA, and 4 additional pts had PSA < 1.0 ng/dL. Twelve pts experienced ≥ Grade 3 adverse events (AEs), 6 AEs were attributed to study intervention including cytopenias (3), hypotension (1), pneumonitis (1), and stenosis of gastrointestinal stoma (1). Unfortunately, two patients deceased on-study (myocardial infarction after 13 weeks, severe SARS-CoV-2 infection after 19 weeks). Conclusions: The Prime-Cut study did not meet its primary endpoint. However, PSA kinetics and results from the pre-planned correlative science demonstrate ongoing role for immunotherapeutic approaches in mHSPC. No new safety signals were observed. Clinical trial information: NCT03951831 .

Real world outcomes of patients treated with first line chemo-immunotherapy (IO) for small cell lung cancer (SCLC): Impact of brain metastases and patterns of subsequent therapy.

e20639 Background: The addition of IO to chemotherapy for first-line treatment of SCLC has improved median overall survival (OS). No OS difference was observed in patients with brain metastases in the clinical trial setting, however outcomes need to be assessed in the non-clinical trial setting. Methods: This retrospective study included 121 patients with SCLC who received ICI-based therapy between 2016-2022 at the Ohio State University. Medical records were extracted via chart review and data was collected in REDCap. Clinical characteristics were summarized using descriptive statistics and compared between patients with and without brain metastasis using Kruskal-Wallis test (continuous outcomes) and Fisher’s exact test (categorical outcomes). Kaplan-Meier survival analysis were used to assess the survival outcomes. All statistical analysis was done in SAS 9.4. Results: Median age at diagnosis was 64.7 years (IQR: 60.1-69.7). Our cohort included 53.8% males and 46.2% females, majority (89.1%) of patients were white, 7.6% were African Americans. Baseline ECOG status was 0 (11.9 %), 1(50%) and > = 2 (38.1%). 97% were current or former smokers. Most had extensive stage disease (96.6%) at diagnosis. Most common sites of metastasis at diagnosis were liver (46.2%), bone (42.9%), brain (35.3%), lymph nodes (34.7%). All patients received first line chemotherapy with atezolizumab (atezo), 40% received atezo with cycle one of chemotherapy, 47% had atezo added with the second cycle, and 13% had atezo added after cycle 2. Median OS for all patients was 9.5 months (95% CI 8.1, 12.9 months); 81% had disease progression at a median follow up of 8.5 months (95% CI 5.2-16.8). 52% patients received second line therapy, 18% received third line and 12% received fourth line and beyond. Subsequent therapies included chemotherapy (29.8%), immunotherapy (4.1%) and clinical trials (14.1%). CNS progression was seen in 47.9%. Median OS for patients with baseline brain metastasis was not significantly different than patients without,11.8 months (95% CI 8-17.6 months) compared to 8.3 months (95% CI 6.2-12.9 months), p:0.26. For patients without baseline brain metastases, median time to developing brain metastasis from starting chemo-IO was 7.3 months [IQR: 5.3-14.1 months]. There was no significant association between the development of brain metastasis and age, sex, or race. At CNS progression 36.4% received SBRT, 18.2% received WBRT. Conclusions: Median overall survival in this cohort was shorter than what has been reported in the phase 3 trials with first line chemo-IO. OS for patients with brain metastases did not differ significantly than for those without, and there was a higher rate of SRS/SBRT versus WBRT. Just over half of patients received subsequent lines of therapy highlighting the need for continued improvement in treatment options for SCLC.

High-dose paclitaxel and its combination with CSF1R inhibitor in polymeric micelles for chemoimmunotherapy of triple negative breast cancer

The presence of immunosuppressive immune cells in tumors is a significant barrier to the generation of therapeutic immune responses. Similarly, in vivo triple-negative breast cancer (TNBC) models often contain prevalent, immunosuppressive tumor-associated macrophages in the tumor microenvironment (TME), resulting in breast cancer initiation, invasion, and metastasis. Here, we test systemic chemoimmunotherapy using small-molecule agents, paclitaxel (PTX), and colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397, to enhance the adaptive T cell immunity against TNBCs in immunocompetent mouse TNBC models. We use high-capacity poly(2-oxazoline) (POx)-based polymeric micelles to greatly improve the solubility of insoluble PTX and PLX3397 and widen the therapeutic index of such drugs. The results demonstrate that high-dose PTX in POx, even as a single agent, exerts strong effects on TME and induces long-term immune memory. In addition, we demonstrate that the PTX and PLX3397 combination provides consistent therapeutic improvement across several TNBC models, resulting from the repolarization of the immunosuppressive TME and enhanced T cell immune response that suppress both the primary tumor growth and metastasis. Overall, the work emphasizes the benefit of drug reformulation and outlines potential translational path for both PTX and PTX with PLX3397 combination therapy using POx polymeric micelles for the treatment of TNBC.

Natural killer cells strengthen antitumor activity of cisplatin by immunomodulation and ameliorate cisplatin-induced side effects

PurposeCisplatin-based chemotherapy is now an important treatment for improving bladder cancer prognosis. However, challenges in clinical treatment remain due to the numerous side effects of chemotherapy. Natural killer (NK) cells regulate certain immune responses and play a significant role in tumor surveillance and control. The efficacy of NK cells combined with cisplatin for chemoimmunotherapy in bladder cancer remains poorly understood.MethodsIn this study, we established an MB49 tumor-bearing mouse model, tumor growth was measured in a control group and in groups treated with cisplatin, NK cells or both. Organ indices, biochemical indicators of blood serum, and expression of apoptotic proteins were used to assess the extent of organ damage. ELISA and immunohistochemistry were used to analyze the levels of immune cells and cytokine expression in serum, spleen, and tumor tissue.ResultsNK cells combined with cisplatin exhibited better antitumor activity. NK cells also alleviated the organ damage caused by cisplatin and improved the survival rate. Treatment with NK cells increased the expression of IL-2 and IFN-γ as well as the number of CD4 + T cells. Additionally, cisplatin increased the expression of natural killer group 2, member D (NKG2D) ligands thus activating NK cells to kill tumor cells.ConclusionNK cells could alleviate the side effects of cisplatin treatment and enhance antitumor activity. The combination of NK cells and cisplatin thus provides a promising option for chemoimmunotherapy for bladder cancer.

Better together? costs of first-line chemoimmunotherapy for advanced non-small cell lung cancer.

Recent advances have created options for first-line (1L) treatment of advanced/metastatic non-small cell lung cancer (aNSCLC). The study objectives were to describe the utilization of 3 classes of 1L treatment-chemotherapy (CT), immunotherapy (IO), and chemoimmunotherapy (IO+CT)-and the total, third-party payer, direct health care costs. Retrospective, administrative claims database analysis of patients with aNSCLC who initiated 1L treatment between January 1, 2017, and May 31, 2019, with IO, CT, or IO+CT. Microcosting enumerated health care resource utilization, including antineoplastic drug costs, using standardized costs. Generalized linear models estimated per-patient per-month (PPPM) costs during 1L treatment, and adjusted cost differences in 1L among treatment cohorts were calculated using recycled predictions. A total of 1317 IO-, 5315 CT-, and 1522 IO+CT-treated patients were identified. Utilization of CT declined from 72.3% to 47.6% between 2017 and 2019, replaced by use of IO+CT, which increased from 1.8% to 29.8%. Total PPPM costs in 1L were highest with IO+CT at $32,436, compared with $19,000 and $17,763 in the CT and IO cohorts, respectively. Adjusted analyses showed that PPPM costs were $13,933 (95% CI, $11,760-$16,105) higher in the IO+CT vs IO cohort (P < .001) and IO costs were $1024 (95% CI, $67-$1980) lower than CT (P = .04). IO+CT accounts for almost one-third of 1L aNSCLC treatment modalities, coinciding with a reduction in treatment with CT. Costs for patients treated with IO were lower than those for patients treated with both IO+CT and CT alone, driven primarily by antineoplastic drug and associated medical costs.

Abstract 6669: Antigen features are associated with response and survival after neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer

Abstract In the Phase II LCCC1520 trial, neoadjuvant chemo-immunotherapy (pembrolizumab with gemcitabine plus cisplatin) induced response in 22 of 39 muscle-invasive bladder cancer patients[1]. In this correlative analysis, we identify molecular features associated with response and survival. Associations of molecular subtype, TMB, and antigen presentation and immune checkpoint gene expression with response and survival were evaluated pre-and post-treatment. Neoantigens were predicted in 4 immuno-oncology data sets (LCCC1520, IMvigor210 cohorts 1[2] and 2[3], and Hugo[4]) using Landscape of Effective Neoantigens Software[5]. Effective neoantigen count (ENC) was calculated by binning predicted neoantigens by expression, binding affinity, binding stability, and tumor PD-1 and PD-L1 expression, then identifying the bin in which neoantigen count was most strongly associated with response in the discovery set. Using elastic net modeling with 10-fold cross-validation, survival was predicted from immune gene signature expression, clinical variables, TMB and ENC. Response was associated with pre-treatment molecular subtype and immune checkpoint expression. Pre-treatment ENC was associated with response in Hugo (discovery set, p = 0.020) and the three validation sets (p = 0.011, 0.042, 0.049). The final elastic net model (Cox P-H p = 5.6e-5) predicted survival significantly better than TMB (p = 0.055) or ENC (p = 0.141) alone. Post-treatment antigen presentation gene expression was associated with survival among non-responders. We identify pre-and post-treatment features associated with response and survival in the LCCC1520 trial and propose that tumor antigen presentation is a major driver of neoadjuvant chemo-immunotherapy outcomes. [1] Rose JCO 2022 [2] Balar Lancet 2017 [3] Mariathasan Nature 2018 [4] Hugo Cell 2016 [5] Vensko bioRxiv 2022 Citation Format: Wolfgang Beckabir, Steven Vensko, Alec Wilkinson, Gatphan Atassi, Mi Zhou, Kenneth Fowler, Leah Flick, Hsing-Hui Wang, Mark Woodcock, Karen McKinnon, Jonathan Serody, Tracy Rose, Matthew Milowsky, William Kim, Benjamin Vincent. Antigen features are associated with response and survival after neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6669.

Prognostic Awareness, Palliative Care Use, and Barriers to Palliative Care in Patients Undergoing Immunotherapy or Chemo-Immunotherapy for Metastatic Lung Cancer.

Background and Objectives: This study describes patients' prognostic awareness and palliative care use in the setting of immunotherapy for metastatic non-small cell lung cancer (mNSCLC). Design: We surveyed 60 mNSCLC patients receiving immunotherapy at a large academic medical center; conducted follow-up interviews with 12 survey participants; and abstracted palliative care use, advance directive completion, and death within a year of survey completion from the medical record. Results: Forty seven percent of patients surveyed thought they would be cured; 83% were not interested in palliative care. Interviews suggested oncologists emphasized therapeutic options when discussing prognosis and that commonly used descriptions of palliative care may exacerbate misperceptions. Only 7% had received outpatient palliative care and 8% had an advance directive a year after the survey; only 16% of the 19 patients who died had received outpatient palliative care. Conclusions: Interventions are needed to facilitate prognostic discussions and outpatient palliative care during immunotherapy. Clinical Trial Registration Number NCT03741868.

Age-Stratified Analysis of First-Line Chemoimmunotherapy for Extensive-Stage Small Cell Lung Cancer: Real-World Evidence from a Multicenter Retrospective Study.

Chemoimmunotherapy improved overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) in two phase III trials. They set the age-stratified subgroup analyses at 65 years; however, over half of the patients with lung cancer were newly diagnosed at ≥75 years in Japan. Therefore, treatment efficacy and safety in elderly patients ≥ 75 years with ES-SCLC should be evaluated through real-world Japanese evidence. Consecutive Japanese patients with untreated ES-SCLC or limited-stage SCLC unfit for chemoradiotherapy between 5 August 2019 and 28 February 2022 were evaluated. Patients treated with chemoimmunotherapy were divided into the non-elderly (<75 years) and elderly (≥75 years) groups, and efficacy, including PFS, OS, and post-progression survival (PPS) were evaluated. In total, 225 patients were treated with first-line therapy, and 155 received chemoimmunotherapy (98 non-elderly and 57 elderly patients). The median PFS and OS in non-elderly and elderly were 5.1 and 14.1 months and 5.5 and 12.0 months, respectively, without significant differences. Multivariate analyses revealed that age and dose reduction at the initiation of the first chemoimmunotherapy cycle were not correlated with PFS or OS. In addition, patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) = 0 who underwent second-line therapy had significantly longer PPS than those with ECOG-PS = 1 at second-line therapy initiation (p < 0.001). First-line chemoimmunotherapy had similar efficacy in elderly and non-elderly patients. Individual ECOG-PS maintenance during first-line chemoimmunotherapy is crucial for improving the PPS of patients proceeding to second-line therapy.

Pathologic response with neoadjuvant chemotherapy, immunotherapy, and chemo-immunotherapy for muscle-invasive bladder cancer (MIBC): A systematic review and meta-analysis.

531 Background: Neoadjuvant cisplatin-based chemotherapy (NAC) is established in the management of MIBC. Pathologic complete response (pCR, ypT0N0) and downstaging (&lt;ypT2N0) are associated with long term survival in patients with MIBC. Several trials have evaluated neoadjuvant immunotherapy (NAI) and chemoimmunotherapy (NACI) for MIBC. We aimed to conduct a meta-analysis of available trials to compare the incidence of pathological response with NAC, NAI and NACI in MIBC patients undergoing radical cystectomy. Methods: Phase II/III clinical trials assessing neoadjuvant systemic therapies (NAC, NAI, or NACI) in patients with MIBC undergoing radical cystectomy were identified through a systematic search of MEDLINE and EMBASE. Outcomes of interest included pCR and pathological downstaging. A DerSimonian and Laird random-effect meta-analysis was conducted to estimate pooled incidence of events using the Freeman-Tukey transformation. Clopper-Pearson method was used to estimate the associated 95% confidence intervals (CI). Results: Of the 5357 records initially identified, 28 trials with a total of 2138 patients were considered eligible for inclusion. Neoadjuvant chemotherapy was assessed in 15 trials (1535 patients), NAI in 5 (288 patients), and NACI in 8 (315 patients). The pooled incidence of patients experiencing a pCR was 30.91% (95% CI: 26.54%-35.45%) with NAC, 30.92% (23.22%-39.14%) with NAI, and 42.25% (36.6%-48.0%) with NACI. The difference in pCR among these therapies was statistically significant (p &lt;0.05). Similarly, the pooled incidence of achieving pathological downstaging was 40.91% (34.26%-47.72%) with NAC, 38.84% (26.73%-51.64%) with NAI, and 62.88% (57.22%-68.39%) with NACI. Consistently, there was statistically significant effect modification by the choice of neoadjuvant systemic therapy (p &lt;0.01). The results were consistent across different clinically important subgroups (Table). Conclusions: NACI may achieve better pCR and pathological downstaging than NAC and NAI alone in MIBC patients which may potentially be associated with long-term survival. Definitive data from phase III trials are pending. [Table: see text]

Injectable zwitterionic cryogels for accurate and sustained chemoimmunotherapy.

Chemoimmunotherapy is an effective method to treat cancer, and thus various vehicles have been constructed to co-deliver immune agents and anticancer drugs. But the immune induction process in vivo is highly susceptible to the influence of the material itself. To avoid immune reactions by the materials of delivery systems, herein, a new kind of zwitterionic cryogels (SH cryogels) with extremely low immunogenicity was prepared for chemoimmunotherapy of cancer. Their macroporous structure enabled the SH cryogels to have good compressibility and be injected through a conventional syringe. The loaded chemotherapeutic drugs and immune adjuvants were accurately, locally and long-termly released in the vicinity of tumors, enhancing the outcome of tumor therapy and minimizing the damage caused by the chemotherapeutic drugs to other organ tissues. In vivo tumor treatment experiments indicated that chemoimmunotherapy using the SH cryogel platform could inhibit the growth of breast cancer tumors to the greatest extent. Furthermore, macropores of SH cryogels supported cells to move freely in the cryogels, which could promote the dendritic cells to capture the in situ produced tumor antigens and present them to T cells. The ability to act as cradles for cell infiltration made the SH cryogels promising for applications as vaccine platforms.

Abstract 9454: Cardiovascular Risks of Chemo-Immunotherapy for Lung Cancer: A Population-Based Cohort Study

Introduction: Chemo-immunotherapy combinations have proven efficacious for treating advanced lung cancer. However, their cardiovascular risks are unclear. This study thus aimed to compare the cardiovascular risks between programmed cell death protein 1 (PD-1) inhibitors, and chemo-immunotherapy in Asian patients with lung cancer. Methods: This retrospective cohort study included patients aged at least 18 years old with lung cancer receiving any PD-1 inhibitor in Hong Kong during 2013-2021. Patients with non-concurrent use of PD-1 inhibitor and chemotherapy, use of tyrosine kinase inhibitor, other immunotherapy, or those with prior stroke, heart failure, or myocardial infarction were excluded. Treatment groups were defined as PD-1 inhibitor only, and concurrent use of PD-1 inhibitor and chemotherapy (chemo-immunotherapy). The endpoint was major adverse cardiovascular events (MACE), that was the first occurrence of cardiovascular death, heart failure, stroke, or myocardial infarction. Patients were followed up until the end of 2021. Inverse probability treatment weighting (IPTW) was used to minimise covariate imbalances. Results: Of the 1508 patients identified, 713 were analysed (538 male, mean age 66.2±10.6 years old, mean follow up 1.4±1.3 years); 333 received PD-1 inhibitors only, and 380 received chemo-immunotherapy. IPTW achieved good balance for all covariates. The observed incidence rate of MACE was 2.8 events per 100 person-year (95% confidence interval (CI) 1.6-4.8) for patients on PD-1 inhibitors, and 2.1 per 100 person-year (95% CI 1.2-3.8) for those on chemo-immunotherapy. The log-rank test showed no significant difference in cumulative incidence of MACE between treatment groups (p=0.641; Figure 1). Conclusions: MACE may be uncommon amongst patients with lung cancer receiving PD-1 inhibitors or chemo-immunotherapy. The associated risks of MACE may not be significantly different between PD-1 inhibitors and chemo-immunotherapy.