Treatment Of Refractory Cancer Research Articles

Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, is effective against tumors poorly responsive to conventional immunotherapy.

Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.

MYC and p53 alterations cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer.

Though immune checkpoint blockade (ICB) therapies can achieve curative responses in many treatment-refractory cancers, they have limited efficacy in CRPC. Here we identify a genetic mechanism by which VEGF contributes to T cell suppression, and demonstrate that VEGFR2 blockade can potentiate the effects of PD-L1 ICB to immunologically treat CRPC.

Broadening Eligibility Criteria for Clinical Trials May Benefit Participating Patients

Results of a review published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR), seem to suggest that patients with treatment-refractory cancers who received eligibility and testing waivers to participate in a large basket/umbrella oncology trial, had similar rates of clinical benefit and adverse events as patients who participated in the trial without waivers.

A phase I trial of intratumoral STX-001: A novel self-replicating mRNA expressing IL-12 alone or with pembrolizumab in advanced solid tumors.

TPS2696 Background: STX-001 is a multi-mechanistic lipid nanoparticle encapsulated synthetic self-replicating mRNA, engineered to express the IL-12 cytokine for an extended duration when administered intratumorally. A murine surrogate of STX-001 induces deep durable responses in multiple preclinical solid tumor models. This Phase 1 open-label, multi-center first-in-human dose-escalation trial evaluates the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of STX-001 alone, or in combination with pembrolizumab in patients with treatment refractory advanced cancers. Methods: Approximately 30 adults ≥18 years of age with histologically confirmed advanced solid tumors that are refractory to standard treatments will be enrolled. The study will consist of two arms, an STX-001 monotherapy arm and an STX-001 + pembrolizumab combination arm, enrolling approximately 15 patients each. Key eligibility criteria include ECOG status 0 or 1, a tumor lesion amendable to injection, and confirmed prior disease progression. STX-001 will be administered every 3 weeks (q3w) for 3 doses and then every 6 weeks (q6w) for a further 3 doses. Tumor biopsies will be obtained at baseline and after the first STX-001 administration. Primary endpoints will include safety and maximum tolerated dose (MTD), with secondary endpoints encompassing pharmacokinetics and preliminary efficacy as measured by RECIST 1.1. To determine the MTD, this study will employ the Bayesian optimal interval (BOIN) design, with the 3 + 3 design run-in and a recommended phase 2 dose (RP2D) will be determined. Tumor response will be assessed using RECIST 1.1 criteria. Exploratory pharmacodynamic analyses will assess tumor-infiltrating lymphocytes and STX-001 mRNA in baseline and on-treatment biopsies, evaluate inflammatory cytokine profiles in plasma, determine immune activation in circulating immune cells, and measure circulating tumor DNA (ctDNA) for molecular response assessment. Clinical trial information: NCT06249048 .

Chemically Induced Brain Cancer in Sprague-Dawley Rats: Changed Lipidomics Mimics the Human Conditions

Malignant gliomas are one of the most treatment-refractory cancers. Development of resistance to chemo- and radiotherapies contributes to these tumors’ aggressive phenotypes. Elevated lipid levels in gliomas have been reported for the last 50 years. However, the molecular mechanisms of how tumor tissues obtain lipids and utilize them are not well understood.In our study, 48.6% of phosphatidylcholines were significantly changed during an early stage of brain cancer in females, and 66.2% in males. As for lysophosphatidylcholines 57.1% metabolites were significantly changed in female, and 64.3% in male rats. We observed the most interesting results in the group of sphingomyelins, where 85.8% metabolites were significantly elevated during brain cancer. According to VIP projection, the most important metabolites were: PC ae C40:3, PC ae C38:1, PC ae C30:1, PC ae C38:3, PC ae C44:3, PC aa C40:2, PC aa C42:0, PC ae C30:2, SM C20:2, PC aa C42:1 in females, and PC ae C38:1, PC ae C40:3, PC ae C30:1, PC ae C42:1, SM C20:2, PC aa C34:4, PC ae C38:4, PC aa C32:2, PC aa C38:5, lysoPC a C14:0. The identification of lipid biomarkers during the early stage of cancer could improve patient prognosis.

Abstract 3979: PD-1 signals regulate NKG7 that is required for CD8+ T cells to sustain cytotoxicity and durable antitumor memory responses

Abstract Cytotoxic CD8+ T cells play a key role in response to anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) therapy. However, the exact effector molecules that are regulated by PD-1 signals in cytotoxic CD8+ T cells have not been completely defined. Lack of this knowledge is a crucial problem in addressing how to overcome the low clinical response rate to ICI therapy. When exploring why certain patients not responding to ICI therapy, we found non-responders did not have an elevated NKG7 expression in CD8+ T cells as responders to ICI therapy. The difference in NKG7 expression in CD8+ T cells between non-responders and responders to anti-PD-1 therapy prompted us to investigate the potential role of PD-1 signaling in regulating NKG7 expression. To that end, we generated a CD8+ T cell-specific Pdcd1 conditional knockout mice (CD8 E8ICre-Pdcd1fl/fl, also known as CD8-PD-1 cKO) where Pdcd1 is deleted after thymic selection of single positive CD8+ T cells. We observed a delayed tumor growth and prolonged survival in CD8-PD-1 cKO mice compared to control mice after B16-OVA melanoma tumor challenge. On Day 12, when the CD8-PD-1 cKO mice demonstrated their ability to control tumor growth, we conducted single cell RNA sequencing on isolated tumor infiltrating CD8+ T cells, revealing a significant increase of Nkg7 expression in effector CD8+ T cells in the Pdcd1 deficient CD8+ T cells compared to the control wild type T cells. Pdcd1-deficient effector CD8+ T cells also had increased expression of genes linked to NFAT/Calcineurin signaling pathway including Nfatc1, S100a4, Tbet and Tox, suggesting Nkg7 could be regulated by Pdcd1 via the NFAT pathway. To determine the impact of increased NKG7 expression in CD8+ T cells, we used OVA protein as a surrogate tumor antigen in vaccination. We found a complete B16-OVA tumor rejection in CD8-PD-1 cKO mice compared to control mice when tumor cells were injected on day 7 after vaccination with OVA protein and poly (I:C) (as an adjuvant), but only a partial rejection on day 21. The CD8-PD-1 cKO mice that were tumor-free for 30-40 days rejected 2nd tumor challenge with B16-OVA tumors. This long-term protection is tumor antigen (OVA) specific because these mice did not reject B16F10 tumor cells that do not express OVA antigen. We also found effector memory CD8+ T cells with high cytotoxicity increased in the spleen of CD8-PD-1 cKO mice after OVA antigen immunization compared to control. In conclusion, we found NKG7 is one of the effector molecules in cytotoxic CD8+ T cells, which can be regulated by PD-1 signals through NFAT signaling. Targeting the PD-1-NFAT pathway may be a new option to overcome low responses of T cells to ICI therapy in treatment of refractory cancer. Citation Format: Zhiming Mao, Joanina Gicobi, Jacob Hirdler, Xin Liu, Michelle Hsu, Emilia Dellacecca, Wenjing Zhang, Fabrice Lucien-Matteoni, Hai dong. PD-1 signals regulate NKG7 that is required for CD8+ T cells to sustain cytotoxicity and durable antitumor memory responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3979.

Abstract 5108: Immunomodulatory and anti-tumor effect of radiation and induced telomere damage to treat pediatric high-grade gliomas

Abstract Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma (DIPG) are among the most treatment refractory cancers in children. Despite multimodal therapy, prognosis is dismal with survival of <1 year for DIPG and a 5-year overall survival <10% for other pHGGs. Radiotherapy remains the only standard of care for DIPG that extends the survival by few months. In recent years, immunotherapy is emerging as a potential alternative treatment option. However, several factors have hindered the use of immunotherapy for pHGGs including “cold” immune environment with lack of immune cells infiltration, low tumor mutational burden, and lack of neo-antigen expression that prevents tumor recognition by the immune system. Therefore, novel therapies that activate the immune system while evading the tumor immunosuppression are highly needed. Here, we aim to demonstrate the immunomodulatory anti-tumor effects of THIO (6-thio-2’deoxyguanosine), a nucleoside analog and a telomerase-dependent telomere targeting agent, in DIPG mouse models. Our preclinical in vitro and in vivo data have demonstrated the efficacy of THIO in inducing telomeric damage, G2/M cell cycle arrest, and apoptosis in high-risk medulloblastoma and DIPG. Importantly, we have demonstrated that THIO crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. THIO was shown to induce anti-tumor immunity through micronuclei formation leading to cGAS-STING pathway mediated activation of the innate and adaptive immune response in colon, lung, and hepatocellular carcinoma tumor models. Our preliminary data demonstrate the THIO-dependent induction of micronuclei formation co-localizing with cGAS and leading to STAT1 activation in DIPG cell lines. We have also shown that THIO synergistically sensitizes DIPG cells to ionizing radiation (IR), significantly decreasing cell proliferation. We are currently testing the combination of THIO+IR in an orthotopic mouse model for DIPG. We will present results on the potential of THIO and IR treatments to stimulate anti-tumor immunity through the activation of STING pathway in a syngeneic mouse model of DIPG. These preclinical studies will support the potential use of THIO and IR to treat children with high-risk pediatric brain tumors. Citation Format: Umaru Banlanjo, Shiva Senthil Kumar, Sergei Gryaznov, Rachid Drissi. Immunomodulatory and anti-tumor effect of radiation and induced telomere damage to treat pediatric high-grade gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5108.

Abstract 720: Combining zelasudil, a small molecule ROCK2 inhibitor, with chemotherapy or immunotherapy improves response in preclinical models of pancreatic cancer

Abstract Zelasudil (RXC007) is an orally available, highly selective small molecule inhibitor of Rho-associated coiled-coil containing protein kinase 2 (ROCK2), which has demonstrated pre-clinical anti-fibrotic efficacy and is currently being tested in a Phase 2a clinical trial for the treatment of idiopathic pulmonary fibrosis (IPF) (NCT05570058). Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and therapeutically challenging disease with a dense and highly fibrotic tumor microenvironment which may limit efficacy of conventional therapies. Here, we investigate the benefit of combining an anti-fibrotic, RXC007, with either standard of care chemotherapy or immunotherapy in mouse models of PDAC.In a fibrotic patient-derived metastatic PDAC orthotopic model, RXC007 (10mg/kg, 50mg/kg and 100mg/kg BID 5d on/2d off PO) in combination with SoC chemotherapy Gemcitabine (100mg/kg IP QW)/Abraxane (30 mg/kg IP QW) improved survival in a dose-dependent manner (all P<0.0001) compared to Gemcitabine/Abraxane alone.In the immunocompetent orthotopic LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) model of metastatic PDAC, survival was significantly increased (P<0.0001) upon treatment with a combination of RXC007 (50 mg/kg BID 5d on/2d off PO) and anti-PD1 (200 ug BIW) compared to anti-PD1 alone. ROCK2 inhibition elicited positive immunomodulatory effects in KPC pancreatic tumors, with increase of CD8+ (P=0.0031) and CD4+ (P=0.008) T cell infiltrate into the tumor cortex and reduction in immunosuppressive FOXP3+ regulatory T cells at the tumor border. Furthermore, RXC007 monotherapy exhibited anti-fibrotic effects, via a decrease in collagen content and organization, effects associated with CAF reprogramming and reduced intra-tumoral aSMA+ PDPN+ myofibroblast-like CAFs (myCAFs; P=0.0406).This data highlights the potential for treating highly fibrotic tumours with RXC007 in combination with SoC chemotherapy or immunotherapy in order to improve patient outcomes in this aggressive and treatment-refractory cancer. Citation Format: Marina Pajic, Benjamin McLean, Diego Chacon Fajardo, Sean Porazinski, Dannielle H. Upton, Diana Schuhmacher, Aji Istadi, Thomas Cox, Paul Timpson, Daniel J. Wilcock, Katie J. Anderson, Helen Mason, Nicolas E. Guisot, Clifford D. Jones, Caroline Phillips, Richard Armer. Combining zelasudil, a small molecule ROCK2 inhibitor, with chemotherapy or immunotherapy improves response in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 720.

Abstract 5086: Functional profiling in lung tumor explants show contributions of the tumor microenvironment to response of Dato-DXdex vivo

Abstract Background: Antibody drug conjugates (ADCs) have demonstrated significant antitumor activity against multiple treatment refractory cancers. While Trastuzumab deruxtecan, a HER2 directed ADC, has shown impressive clinical activity in HER2-expressing cancers, the ability to predict responses of ADCs by IHC has been limited. Dato-DXd is a TROP2 directed ADC that is currently being studied in a number of registrational phase 3 trial incld. TROPION-Lung01. In the phase 1b TROPION-Pan tumor 01 trial (TP01) response to Dato-DXd did not correlate to TROP2 IHC expression. Here we investigate molecular determinants of sensitivity to Dato-DXd using short-term microfluidic culture of patient derived organotypic tumor spheroids (PDOTS). Methods: Surgical NSCLC cases collected from Brigham and Women’s Hospital and St. Elizabeth’s Medical Center under an IRB approved protocol were studied. PDOTS were generated as previously described. Ex vivo response was assessed by live/dead imaging, TROP2 antigen density on EPCAM+ cells by flow cytometry (FCM) and by immunofluorescence (IF). T cell and myeloid cell populations were analyzed by FCM of CD45+ cells isolated during tumor preparation. For a subset of samples single cell RNA sequencing (scRNAseq) was performed. Results:Eleven NSCLC explants were studied. Two specimens were excluded due to excess of fibrotic material. Response to Dato-DXd was measured by change in raw live cell area compared to control samples. Median response to Dato-DXd was -48.5% (ranging from +33.9% to -77.8%). Using a cut-off of -40%, four cases were characterized as non-responders (NR) and 5 as responders (R). Tumor TROP2 expression by IF ranged from 0 to 3+ with no relationship between TROP2 expression and response being observed. TROP2 staining positivity by IF didn’t correlate to Dato-DXd sensitivity ex vivo. TROP2 FCM, on the other hand discriminated between responsive and non-responsive models in 100% of the cases, using a cutoff of MFI >13000. Furthermore, we observed an increase of tumor CD8 abundance in Dato-DXd R compared to NR (median %CD8 in R 10.3% (range 5.1%-62.5%); median %CD8 of live cells in NR 2.3% (range 1.2%-3.7%) p-value 0.029). Conversely, we also observed a trend of higher granulocytic myeloid-derived suppressor cells abundance in NR compared to R (NR median %gMDSC of CD15+ cells 84.1% (range 73.4%-90.2%) ; R median %gMDSC 61.7% (range 54.3%-90.6%); p-value 0.069). In 2 cases with high and low TROP2 MFI available scRNAseq data showed TROP2 expression exclusively in tumor cells, with further analysis ongoing. Conclusion: By functionally profiling NSCLC PDOTS that retain immune cells, we correlated multiple parameters with ex vivo response to Dato-DXd. Our results have important implications for precision deployment of ADCs and suggest that target tumor antigen density in conjunction with addition immune cell features may refine patient selection strategy. Citation Format: Satoru Yasuda, Elena Ivanova, Ha V. Vo, Sophie Kivlehan, Iliana Gjeci, Minh Ha, Patrick Lizotte, Raphael Bueno, David A. Barbie, Cloud P. Paweletz. Functional profiling in lung tumor explants show contributions of the tumor microenvironment to response of Dato-DXdex vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5086.

Exploring the next generation of antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a promising cancer treatment modality that enables the selective delivery of highly cytotoxic payloads to tumours. However, realizing the full potential of this platform necessitates innovative molecular designs to tackle several clinical challenges such as drug resistance, tumour heterogeneity and treatment-related adverse effects. Several emerging ADC formats exist, including bispecific ADCs, conditionally active ADCs(also known asprobody-drug conjugates), immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs, and each offers unique capabilities for tackling these various challenges. For example, probody-drug conjugates can enhance tumour specificity, whereas bispecific ADCs and dual-drug ADCs can address resistance and heterogeneity with enhanced activity. The incorporation of immune-stimulating and protein-degrader ADCs, which have distinct mechanisms of action, into existing treatment strategies could enable multimodal cancer treatment. Despite the promising outlook, the importance of patient stratification and biomarker identification cannot be overstated for these emerging ADCs, as these factors are crucial to identify patients who are most likely to derive benefit. As we continue to deepen our understanding of tumour biology and refine ADC design, we will edge closer to developing truly effective and safe ADCs for patients with treatment-refractory cancers. In this Review, we highlight advances in each ADC component (the monoclonal antibody, payload, linker and conjugation chemistry) and provide more-detailed discussions on selected examples of emerging novel ADCs of each format, enabled by engineering of one or more of these components.

Correction: Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: a Phase I Dose Escalation and Expansion Study

Correction: Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: a Phase I Dose Escalation and Expansion Study

Smoking induces WEE1 expression to promote docetaxel resistance in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) patients have poor clinical outcomes, with an overall 5-year survival rate of 20%. Smoking is a significant risk factor for EAC. The role of WEE1, a nuclear kinase that negatively regulates the cell cycle in normal conditions, in EAC tumorigenesis and drug resistance is not fully understood. Immunohistochemistry staining shows significant WEE1 overexpression in human EAC tissues. Nicotine, nicotine-derived nitrosamine ketone, or 2% cigarette smoke extract treatment induces WEE1 protein expression in EAC, detected by western blot and immunofluorescence staining. qRT-PCR and reporter assay indicates that smoking induces WEE1 expression through miR-195-5p downregulation in EAC. ATP-Glo cell viability and clonogenic assay confirmed that WEE1 inhibition sensitizes EAC cells to docetaxel treatment invitro. A TE-10 smoking machine with EAC patient-derived xenograft mouse model demonstrated that smoking induces WEE1 protein expression and resistance to docetaxel invivo. MK-1775 and docetaxel combined treatment improves EAC patient-derived xenograft mouse survival invivo. Our findings demonstrate, for the first time, that smoking-induced WEE1 overexpression through miRNA dysregulation in EAC plays an essential role in EAC drug resistance. WEE1 inhibition is a promising therapeutic method to overcome drug resistance and target treatment refractory cancer cells.

Serial multiomic analysis in advanced breast cancer: A novel platform to inform therapeutic decisions.

e13001 Background: We designed and implemented a platform wherein patients with metastatic treatment-refractory cancer would receive individually tailored treatment informed by multi-omic data and iteratively adapted in real-time. Here we describe the workflow of this platform and quantify operational characteristics for a metastatic breast cancer cohort. Methods: Participants with metastatic breast cancer progressing after standard-of-care therapy were enrolled. Sites demonstrating disease progression were targeted for biopsy. Resultant tissue was analyzed by a next-generation sequencing (NGS) solid tumor panel, whole exome sequencing, whole transcriptomic sequencing, multiplex protein analysis of a panel of cancer-relevant proteins and phosphoproteins, and focused immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) analysis. Results: Between 1/1/2017 to 12/31/2021, 74 participants were consented and 55 were enrolled. Median age at enrollment was 54 years, most were ECOG 0-1, and received a median of 2 lines of therapy in the metastatic setting. There were 95 biopsies collected from 55 individual participants and analytics were successfully generated in 94% of the cases. At the provider’s request, an integrated clinical, molecular, and cancer biology tumor board (TB) was convened for 25 participants. A total of 21 participants received matched therapy based on clinical parameters coupled to a consideration of biologically informed therapeutic vulnerabilities and 6 had a PFS2/PFS1 > 1.3. Twenty-one participants had a median of 2 repeat progression biopsies (range 2-5) and new alterations with potential therapeutic implications were identified. Repeat biopsies could have led to a new treatment in 11 of the participants, though only 3 received a therapy recommended by the tumor board owing to either rapid disease progression, clinical deterioration, or lack of access to drug. Conclusions: We demonstrated the practical feasibility and initial operating characteristics of a platform designed to comprehensively understand and integrate the clinical and molecular characteristics of a cohort with metastatic progressive breast cancer as they evolve on therapy and to use this information to deliver iteratively tailored therapy in real time. Further, clinical responses were observed in a subset of participants. These findings suggest an opportunity to incorporate this platform earlier in a disease course or to design adaptive clinical trials with access to therapies aimed at targeting new biological alteration.

A Phase I/II Trial of HER2 Vaccine-Primed Autologous T-Cell Infusions in Patients with Treatment Refractory HER2-Overexpressing Breast Cancer.

High levels of type I T cells are needed for tumor eradication. We evaluated whether the HER2-specific vaccine-primed T cells are readily expanded ex vivo to achieve levels needed for therapeutic infusion. Phase I/II nonrandomized trial of escalating doses of ex vivo-expanded HER2-specific T cells after in vivo priming with a multiple peptide-based HER2 intracellular domain (ICD) vaccine. Vaccines were given weekly for a total of three immunizations. Two weeks after the third vaccine, patients underwent leukapheresis for T-cell expansion, then received three escalating cell doses over 7- to 10-day intervals. Booster vaccines were administered after the T-cell infusions. The primary objective was safety. The secondary objectives included extent and persistence of HER2-specific T cells, development of epitope spreading, and clinical response. Patients received a CT scan prior to enrollment and 1 month after the last T-cell infusion. Nineteen patients received T-cell infusions. Treatment was well tolerated. One month after the last T-cell infusion, 82% of patients had significantly augmented T cells to at least one of the immunizing epitopes and 81% of patients demonstrated enhanced intramolecular epitope spreading compared with baseline (P < 0.05). There were no complete responses, one partial response (6%), and eight patients with stable disease (47%), for a disease control rate of 53%. The median survival for those with progressive disease was 20.5 months and for responders (PR+SD) was 45.0 months. Adoptive transfer of HER2 vaccine-primed T cells was feasible, was associated with minimal toxicity, and resulted in an increased overall survival in responding patients. See related commentary by Crosby et al., p. 3256.

Neurosurgical interventions for cancer pain.

Half of all cancer patients will develop cancer-related pain, and a fifth of these patients will continue to experience pain refractory to maximal pharmacological therapy. This, together with the opioid crisis, has prompted a resurgence in neurosurgical treatments. Neuromodulatory or neuroablative procedures are largely used for various nonmalignant, chronic pain conditions, but there is growing evidence to support their use in cancer pain. This review aims to cover the main neurosurgical treatments that may prove useful in the changing sphere of cancer pain treatment. Neuromodulation techniques for pain have largely replaced neuroablation in neurosurgical practice due to the higher risk of inadvertent permanent neurological deficits from the latter. When compared to neuroablative approaches for severe treatment-refractory cancer pain, neuromodulation is more expensive (largely due to implant cost) and requires more follow-up, with greater engagement needed from the health service, the patient and their carers. Furthermore, neuroablation has a more rapid onset of effect. Neuromodulation techniques for pain have largely replaced neuroablation in neurosurgical practice due to the higher risk of inadvertent permanent neurological deficits from the latter. Whilst this approach is beneficial when treating nonmalignant pain, neuromodulation in patients with pain related to advanced cancer still has a limited role. Neuroablative procedures are less expensive, require less follow-up, and can have a lower burden on health services, patients and their carers.

Abstract 5854: Suppression of phosphorylated focal adhesion kinase+ (pFAK+) fibroblasts and C-X-C chemokine receptor type 4 (CXCR4) expressing granulocytes is associated with exceptional clinical outcomes in pancreatic ductal adenocarcinoma (PDAC)

Abstract Background: PDAC is an aggressive and treatment-refractory cancer due to its desmoplastic and immunosuppressive tumor microenvironment (TME). Overexpression of pFAK, a master regulator of the TME, and CXCR4, a receptor involved immunosuppression and tumor progression, are associated with poorer outcomes in PDAC. Exceptional responders, broadly defined by extended survival and durable treatment responses, represent a rare subset in PDAC. We hypothesize that the immune and stromal signatures of exceptional responders vary significantly from non-exceptional responders, specifically exhibiting decreased p-FAK and CXCR4 expression and decreased immunosuppressive myeloid phenotypes in the TME. Methods: We performed correlative quantitative analysis of multiplex immunohistochemistry (mIHC) employing 40 biomarkers on stage I/II PDAC, surgically resected formalin-fixed paraffin-embedded tissues from 9 non-exceptional responders and 11 exceptional responders. Exceptional responders were selected based on degree and duration of disease-free survival or overall survival more than double the historical matched medians. mIHC and image cytometry were used to distinguish and quantify total immune cell populations and colocalize biomarker expression across each distinct cell type. Cell populations and expression levels were compared using unpaired T-tests. Results: Exceptional responders showed significantly decreased overall pFAK expression (p=0.02) and overall CXCR4 expression (p=0.04). In exceptional responders, pFAK expression and CXCR4 expression were significantly decreased in immunosuppressive CD66b+ granulocytes (p=0.01, p=0.03, respectively) and in tumor associated macrophages (p=0.01, p=0.006, respectively). While not significant, exceptional responders demonstrated a marked decrease in immunosuppressive pFAK+ fibroblasts (p=0.12) when compared to non-exceptional responders. No change was seen in the CD8+ T cell infiltration between groups; however, a trend was observed towards an increased proportion of granzyme B+ CD3+ CD8+ cytotoxic lymphocytes (p=0.57) in exceptional responders. Conclusion: Exceptional responders selected in this preliminary study have significantly lower FAK and CXCR4 expression and markedly reduced populations of immunosuppressive FAK+ and CXCR4+ myeloid cells. Suppression of pFAK and CXCR4 in fibroblasts and granulocytes, respectively are associated with exceptional clinical outcomes. Future expanded research comparing the distinct TME and genetic signatures of exceptional responders to non-exceptional is warranted. Citation Format: John Davelaar, Anser A. Abbas, Angela Minasyan, Omer H. Elmadbouh, Natalie Moshayedi, Brent Larson, Nicholas Nissen, Simon Lo, Srinivas Gaddam, Kambiz Kosari, Jun Gong, Andrew Hendifar, Stephen Pandol, Arsen Osipov. Suppression of phosphorylated focal adhesion kinase+ (pFAK+) fibroblasts and C-X-C chemokine receptor type 4 (CXCR4) expressing granulocytes is associated with exceptional clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) [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 5854.

Trial in progress: A phase 2 study of CTX-009 in adult patients with metastatic colorectal cancer who have received two or three prior systemic chemotherapy regimens.

TPS281 Background: CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Patients with unresectable locally advanced and unresectable metastatic colorectal cancer (CRC) are sequentially treated with various combinations or single agent courses of cytotoxic chemotherapy agents including 5-fluorouracil and its orally administered family members (capecitabine, TAS-102) oxaliplatin, and irinotecan, as well with targeted therapies such as bevacizumab or aflibercept (anti-VEGF), cetuximab or panitumumab (anti-EGFR), or multitargeted tyrosine kinase inhibitors (regorafenib). In subsets of patients who have had multigene panel testing done and whose tumors have been identified as having mutations that drive their disease such as defective mismatch repair, HER-2 overexpression, or NTRK fusions specific treatments with respectively PD-1 or PD-L1 inhibitors, traztuzumab or larotrectinib or entrectinib can also be used effectively. Despite the approval of multiple new agents in the past two decades, the goals of therapy are generally palliative although some patients will have long disease-free intervals when they respond to therapy. In the cases of patients whose disease has progressed, or who have not tolerated 2 or 3 prior lines of therapy, the expectation for tumor response with the available treatments are less than 5% and the median overall survival is approximately 6 months (for 3rd line therapy) or less (for 4th line therapy). In a Phase 1 study with CTX-009, responses have been seen in patients with colorectal cancers who were treated in the 4th line setting. Since CTX-009 targets tumor induced neoangiogenesis, and monoclonal antibodies that target vascular endothelial growth factor (VEGF) has been shown to extend the lives of patients with advanced colorectal cancer, testing of CTX-009 in the setting of advanced treatment refractory colorectal cancer is justified. Methods: CTX-009 is being evaluated in an open label study in patients with previously treated metastatic CRC. This study is designed as an adaptive Simon Two Stage study, with approximately 37 patients to be enrolled into Stage 1. If criteria are met to move to Stage 2, an additional 47 patients will be enrolled, for a total of approximately 84 patients. To move to stage 2 of the study, 3 or more Complete or Partial Responses must be confirmed via RECIST 1.1. Patients will be treated in 28-day cycles, with CTX-009 administration on Day 1 and 15. The primary objective of the study is to assess the efficacy of CTX-009, as measured by Overall Response Rate (ORR). The study is currently activating sites with first patient in expected in 2022. Clinical trial information: NCT05513742 .

194P Thermal ablation followed by intratumoral injection of a novel immune stimulant IP-001 in patients with advanced solid tumors: Phase IB part of study SAKK 66/17

The induction of immunogenic cell death by thermal ablation (TA) with local immunostimulation is a novel approach to address advanced, immune “cold”, treatment-refractory cancer. Glycated N-acetylglucosamine polymer, IP-001® , is a novel immune stimulant that drives the activation of innate immune cells through multiple pathways (Stimulator of Interferon Genes STING, Inflammasome, and others) and acts as an antigen depot, which may enhance downstream adaptive anti-tumor immunity. When combined with TA, IP-001 stimulated abscopal effects at distant, untreated tumors, and immune memory in animal models.

Methadone switching for refractory cancer pain

BackgroundMethadone is commonly considered an alternative opioid treatment for refractory cancer pain. This study aims to investigate the efficacy, safety, and cost of methadone in the treatment of refractory cancer pain.MethodsA retrospective study was conducted in patients who used methadone for refractory cancer pain from April 2016 to December 2020 at a cancer specialized hospital. Pain control, evaluated via pain score and breakthrough pain frequency, and adverse events of methadone were compared with analgesic regimens prior to methadone administration. The factors potentially affecting the switching outcome were analyzed via multivariate analysis. Moreover, the cost of pain control was estimated.ResultsNinety patients received methadone for poor pain control (74.4%), intolerable adverse events (10.0%), or both (15.6%) after prior opioid treatments. Sixty-four patients (71.1%) were successfully switched to methadone with median pain score significantly decreased from 4.0 to 2.0 (p < 0.001) and median daily frequency of breakthrough pain from 3.0 to 0.0 (p < 0.001) at a maintained median conversion ratio of 6.3 [interquartile range (IQR): 4.0–10.0] to prior opioid treatment. Similar adverse event profiles of constipation, nausea, vomiting, and dizziness were observed between methadone and prior opioid regimens. The median daily cost of analgesic regimens was significantly reduced from $19.5 (IQR: 12.3–46.2) to $10.8 (IQR: 7.1–18.7) (p < 0.01) after switching to methadone. The 3-day switch method significantly improved the rate of successful switching compared with the stop and go method (odds ratio = 3.37, 95% CI: 1.30–8.76, p = 0.013).ConclusionMethadone is an effective, safe, and cost-saving treatment for patients with refractory cancer pain.

Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma.

Classical MCL (cMCL) constitutes 6–8% of all B cell NHL. Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes. We treated 13 bMCL patients with combined epigenetic and immunotherapy treatment consisting of vorinostat, cladribine and rituximab (SCR). We report an increased OS greater than 40 months with several patients maintaining durable remissions without relapse for longer than 5 years. This is remarkably better then current treatment regimens which in bMCL range from 14.5-24 months with conventional chemotherapy regimens. We demonstrate that the G/A870 CCND1 polymorphism is predictive of blastic disease, nuclear localization of cyclinD1 and response to SCR therapy. The major resistance mechanisms to SCR therapy are loss of CD20 expression and evasion of treatment by sanctuary in the CNS. These data indicate that administration of epigenetic agents improves efficacy of anti-CD20 immunotherapies. This approach is promising in the treatment of MCL and potentially other previously treatment refractory cancers.