Immunother Cancer Research Articles

A phase 1/2 study of BDC-3042, a novel dectin-2 agonistic antibody, in patients with advanced cancers.

TPS2695 Background: Tumor-associated macrophages (TAMs) are a major component of the immune infiltrate in most cancers and play a key role in establishing the immunosuppressive tumor microenvironment (TME) that enables tumor progression. However, TAMs are phenotypically plastic and have the potential to be reprogrammed into immunostimulatory cells that enhance innate and adaptive anti-tumor immunity. BDC-3042 is a novel agonistic antibody targeting an immune-activating receptor expressed on TAMs known as Dectin-2 ( CLEC6A) [1]. Dectin-2 is a C-type lectin receptor best known for its role in pathogen recognition and induction of protective immune responses against fungi and other microbes. We have previously demonstrated that Dectin-2 agonism stimulates pro-inflammatory cytokine secretion and antigen presentation by TAMs, resulting in robust CD8+ T cell-mediated anti-tumor immunity in syngeneic mouse models [2]. Elevated gene expression of Dectin-2 has been found in a wide range of solid tumor types compared to non-malignant tissues. Nonclinical studies with BDC-3042 have demonstrated its potential to reprogram TAMs and elicit anti-tumor activity as a novel immunotherapeutic approach for diverse human cancers [2]. A phase 1/2, first-in-human, dose-escalation and dose-expansion study of BDC-3042 as a single agent and in combination with a cemiplimab in subjects with advanced cancers has been initiated. Methods: This study is enrolling up to 185 patients with advanced cancers, including non-small cell lung cancer, melanoma, triple-negative breast cancer, renal cell carcinoma, colon cancer, head and neck cancer, and ovarian cancer. Primary objectives of the dose-escalation phase are to define safety and tolerability and to determine the recommended phase 2 dose (RP2D) of BDC-3042 as a monotherapy (Part 1) and in combination with cemiplimab (Part 2). The dose-expansion phase will evaluate preliminary anti-tumor activity of BDC-3042 monotherapy (Part 3) and with cemiplimab (Part 4). Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. Exploratory analyses will also be conducted to assess BDC-3042’s ability to reprogram TAMs and identify biomarkers associated with BDC-3042 biological activity and with cemiplimab. This study is being conducted in the US and is currently recruiting patients. 1. Kenkel J, et al. Cancer Res. 2023. 2. Kenkel J, et al. J Immunother Cancer. 2021. Clinical trial information: NCT06052852 .

A phase 3 trial of IMC-F106C (PRAME x CD3) plus nivolumab versus standard nivolumab regimens in HLA-A*02:01+ patients with previously untreated advanced melanoma (PRISM-MEL-301).

TPS9602 Background: Current standard of care in newly diagnosed patients with metastatic cutaneous melanoma (CM) include anti-PD1 as monotherapy or in combination with other immune checkpoint inhibitors (ICI). However, most patients will eventually progress and the 5-year survival rate remains low, necessitating new therapies with novel mechanisms of action to combine with anti-PD1. T cell receptor (TCR) bispecifics have shown overall survival (OS) benefit with tebentafusp (gp100 ´ CD3) in a phase (Ph) 3 trial in metastatic uveal melanoma [1]. IMC-F106C is the first TCR bispecific protein targeting CD3 and PRAME (PRAME ´ CD3), redirecting T cells towards cancer cells presenting a PRAME peptide on the cell surface by HLA-A*02:01 proteins. PRAME is expressed in the vast majority of melanoma. In an ongoing Ph 1 study (NCT04262466), IMC-F106C monotherapy was well tolerated and demonstrated evidence of durable clinical activity in heavily pre-treated, advanced melanoma patients, including those who progressed on prior ICI and targeted therapy [2]. Two doses, 40 mcg and 160 mcg, were selected for further study based on exposure response modeling. Safety of combination TCR bispecifics with ICI has been demonstrated in the ongoing IMC-F106C Ph 1 study and in a prior study of tebentafusp + ICI [3]. Combining IMC-F106C with the anti-PD1 ICI nivolumab has the potential to improve progression free survival (PFS), OS, and response rate (RR). Methods: PRISM-MEL-301 is a randomized, global, open-label, Ph 3 study in previously untreated HLA-A*02:01+ patients with unresectable or metastatic non-uveal melanoma; up to 10% of patients can have a diagnosis of mucosal, acral, or other non-CM melanoma. The first 90 patients will be randomized 1:1:1 to receive IMC-F106C 40 mcg + nivolumab (Arm A), IMC-F106C 160 mcg + nivolumab (Arm B), or a nivolumab regimen (Arm C) from which a final IMC-F106C dose (Arm A or B) will be selected. Subsequently, approximately 590 additional patients will be randomized to Arm (A or B) vs. control Arm C, either nivolumab monotherapy or nivolumab + relatlimab, dependent on the country. Randomization will be stratified by 1) American Joint Committee on Cancer (8th Edition) M stage with lactate dehydrogenase (LDH; M0 or M1 with normal LDH vs M1 with elevated LDH); 2) prior anti-PD[L]1 adjuvant therapy (yes vs no); and 3) BRAF V600 mutation status (positive vs negative). Primary endpoint is PFS per RECIST 1.1 by blinded independent central review. Secondary endpoints include OS, ORR, and safety. Enrollment is ongoing globally. Clinical trial registration: NCT06112314 Nathan et al. N Engl J Med 2021; 385:1196 Hamid et al. Ann Oncol 2022; 33 (Supp7): S875 Hamid et al. J Immunother Cancer 2023; 11(6): e006747. Clinical trial information: NCT06112314 .

Three-year survival data from a phase 2 trial of neoadjuvant short-course radiotherapy followed by chemotherapy and camrelizumab in locally advanced rectal cancer.

e15611 Background: For locally advanced rectal cancer (LARC), short-course radiotherapy (SCRT) or long-course chemoradiotherapy combined with chemotherapy have been the established neoadjuvant treatment, but the optimal therapeutic modality is still under exploration. We previously reported the short-term results of neoadjuvant SCRT followed by chemotherapy and camrelizumab (a PD-1 inhibitor), encouragingly noting pathological complete response (pCR) in 48.1% of LARC patients (Lin Z et al. J Immunother Cancer 2021;9:e003554). Here, we report the further 3-year follow-up results. Methods: Adult patients with histologically confirmed T3-4N0M0 or T1-4N+M0 rectal adenocarcinoma were enrolled. Prior to surgery, eligible patients received 5×5 Gy SCRT, and after one week, they were treated with camrelizumab (200 mg, i.v., on day 1) plus CAPOX chemotherapy (oxaliplatin 130 mg/m2, i.v., on day 1 and capecitabine 1000 mg/m2, orally, bid, on days 1-14) in 21-day cycles for 2 cycles. Radical surgery was performed one week after the last neoadjuvant cycle. For this updated analysis, disease-free survival (DFS) and overall survival (OS) at 3 years are reported. Results: Thirty patients were enrolled and received SCRT, and all of these patients were included in this OS analysis. Among them, 27 patients received camrelizumab plus CAPOX chemotherapy, all of whom underwent surgery and were included in this DFS analysis. Of the 27 patients, 21 patients (77.8%) received at least one cycle of postoperative adjuvant chemotherapy with CAPOX regimen. With a median follow-up of 40.8 months (IQR 40.3-44.3), disease recurrence or death occurred in six (22.2%) patients. The median DFS and OS were both not reached, with the 3-year DFS and OS rates of 80.2% (95% CI 58.6-91.3) and 93.3% (95% CI 75.9-98.3), respectively. Subgroup analysis showed that patients with pCR, postoperative pathological node-negative status, PD-L1 combined positive score ≥ 1, and negative circumferential resection margin and negative extramural venous invasion by MRI at baseline had a tendency towards improved 3-year DFS and OS compared to those without these characteristics. No new or long-term safety signals were identified. Conclusions: With 3 years of extended follow-up, a favorable survival benefit was observed with neoadjuvant SCRT combined with subsequent CAPOX plus camrelizumab followed by delayed surgery in LARC patients. A randomized phase 3 trial (NCT04928807) is ongoing to confirm these results. Clinical trial information: NCT04231552 .

Abstract 6639: Mechanisms of action of a killed, bacteria-based, multiple immune receptor agonist in development for pulsed anti-tumor immunotherapy

Abstract Activation of immune receptors, such as Toll-like (TLR), NOD-like (NLR) and Stimulator of Interferon Genes (STING) is required for efficient innate and adaptive immunity. Gram-negative bacteria (G-NB) contain multiple TLR, NOD and STING agonists. Potential utility of G-NB for cancer immunotherapy is supported by observations of tumor regression in the setting of infection and Coley’s Toxins. Coley reported that intravenous (i.v.) administration was likely most effective but produced toxicity. The discovery of TLRs and their agonists, particularly the potent/multi-functional TLR4 agonist lipopolysaccharide (LPS)-endotoxin, comprising ~75% of the outer membrane of G-NB, suggests that it may be both a critical active ingredient and responsible for dose-limiting toxicity of i.v. G-NB. We have produced killed, intact bacteria products from non-pathogenic G-NB with ~90% reduction of LPS activity. One product, Decoy10, contained TLR2,4,8,9, NOD2 and STING agonist activity and exhibited reduced i.v. toxicity in mice and rabbits relative to unprocessed cells. Decoy10 and closely related Decoy20 produced single agent activity or combination-mediated durable regressions, with immunological memory, in mice with syngeneic or human breast, colorectal, hepatocellular, pancreatic carcinomas or non-Hodgkin’s lymphoma. Regressions were observed in combination with chemotherapy, a non-steroidal anti-inflammatory drug, anti-PD-1, or rituximab, were associated with induction of 18-26 plasma cytokines/chemokines, activation of innate and adaptive immune pathways in tumors, and were dependent on NK, CD4+ and CD8+ T cells (Newman, Cancer Res 2023;83(7 Suppl):Abstract nr 4165). These and preliminary clinical results demonstrating rapid clearance of Decoy20 with transient induction of >50 plasma cytokines/chemokines (Newman et al., J Immunother Cancer 2023;11(Suppl 2)782-E:A1770) are supportive of a “pulse-prime” mechanism, whereby Decoy bacteria produce transient, but broad innate and adaptive immune activation. We have now analyzed immune activation by Decoy bacteria in vitro using human peripheral blood mononuclear cells (PBMCs). Decoy10 enhanced polarization of CD14+ monocytes to M1 macrophages and inhibited Treg polarization. Decoy10 enhanced monocyte-derived dendritic cell maturation and enhanced Th1, Th2 and Th17 CD4+ polarization, with Th1 at 10-100-fold lower Decoy10 concentrations than Th2 or Th17. Decoy10 also activated NKT and T cells, and enhanced PBMC-mediated tumor cell killing. The results demonstrate that Decoy bacteria stimulate polarization, maturation, or activation of cellular mediators of innate and adaptive anti-tumor immune responses, inhibit an immune-suppressive mechanism, and enhance immune cell killing of tumor cells. The results are consistent with and significantly extend our previously reported in vivo data. Citation Format: Michael J. Newman, Deepak Singh. Mechanisms of action of a killed, bacteria-based, multiple immune receptor agonist in development for pulsed anti-tumor immunotherapy [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 6639.

Abstract 5522: Elucidating the role of P-selectin/P-selectin ligand-1 axis in lung cancer brain metastasis

Abstract Lung cancer (LC) stands as a prominent cause of cancer-related mortality. Brain metastasis (BM) is a common occurrence in LC, constituting nearly 50% of all BM cases with the brain emerging as the preferred site for LC metastasis. Unfortunately, current LCBM treatment options yield limited success, as reflected in the median survival of BM patients at 7.8 months. Consequently, there is an imperative need for novel and more efficacious therapeutic approaches targeting LCBM. Evidence suggests that brain microenvironment cells, particularly microglia and tumor-associated macrophages (TAMs), play a pivotal role in facilitating the colonization and growth of LCBM. Previous investigations from our lab have identified the involvement of the P-selectin/P-selectin glycoprotein ligand-1 (SELP/PSGL-1) axis in microglia/TAMs immunophenotypes, promoting pro-tumorigenic activity. This led us to explore the role of the SELP/PSGL-1 axis in the interactions between LCBM cells and the brain microenvironment1. Thus, we conducted Immunostaining on human tissue samples, revealing increased expression of SELP, PSGL-1, PD-1, PD-L1, IBA-1, and CD68 in LCBM tissues. Simultaneously, we employed advanced 3D models to investigate the intricate interactions between cancer cells and microglia/TAMs. Actively inhibiting the SELP/PSGL-1 axis with pharmacological agents led to a significant decrease in migration and invasion when LC cells were co-cultured with microglia and TAMs. Moreover, SELP inhibition prompted a shift in microglia/TAMs state towards an M1-like phenotype, enhancing the ability of CD4/CD8 cells to target cancer cells in our unique 3D LCBM models. This effect was further enhanced when co-treated with a PD-1 inhibitor, demonstrating a potential synergistic impact in targeting both pathways for therapeutic intervention. Our results suggest that combining SELP inhibition with other immunomodulators, including a small molecule PD-L1 inhibitor developed in our lab2, could synergistically enhance both innate and adaptive anti-tumor immune responses. Taken together, this study may enhance our understanding of LCBM immunogenicity and contribute to the development of novel immunotherapeutic approaches that can improve patient outcomes.1.Yeini, E., et al. P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression. Nat Commun 12, 1912 (2021). 2. Acúrcio, R.C., et al. Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment. J Immunother Cancer 10(2022). Citation Format: Koren Salomon, Eilam Yeini, Neta Frommer, Irisi Kamer, Jair Bar, Iris Barshack, Ronit Satchi-Fainaro. Elucidating the role of P-selectin/P-selectin ligand-1 axis in lung cancer brain metastasis [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 5522.

A Phase 1 Study of CD38-Bispecific Antibody (XmAb18968) for Patients with Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia

Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has remained poor. CD38 is a transmembrane glycoprotein that is highly expressed in T-ALL and is potentially targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We designed a phase I clinical trial to assess the safety and tolerability of XmAb18968 in patients with T-ALL. Methods: We conducted a multicenter, open label, phase I dose escalation study of XmAb18968 (NCT05038644). Patients aged ≥18 years with relapsed/refractory T-ALL or T-lymphoblastic lymphoma (T-LBL), ECOG PS 0-2 and adequate organ function were eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, prior therapy with daratumumab in the last 6 months and active acute graft-versus-host disease. Dose escalation was conducted using 3+3 design, and 4 separate dose levels were studied [0.8mg, 1mg, 1.3mg, 1.5mg]. XmAb18968 was administered intravenously on days 1, 8, 15, 22 on a 28-day cycle. During cycle 1 alone, day 1 dose was fractionated and administered over 2 days to minimize the risk of significant cytokine release syndrome (CRS). Treatment was continued until progression or unacceptable toxicity. The primary objective was to determine the safety and dose limiting toxicity (DLT) and secondary objective was to determine the preliminary efficacy. Correlative studies included pharmacokinetics, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy, and direct glycopeptide analysis. Results: Four patients with relapsed/refractory T-ALL have been enrolled so far at dose level 1 (0.8mg) with 3 of them being evaluable for response (one patient came off study before DLT period). Median age was 62 years (34-74), all response evaluable patients had early T-precursor ALL (ETP-ALL), and one patient (25%) was previously treated with allogeneic HCT, CD7 CAR-T therapy and daratumumab. Grade 3 or higher adverse events are summarized in Table 1. CRS grades 1 was noted in 25% of patients, no grade ≥3 CRS or neurotoxicity (any grade) was seen. Of the 3 evaluable total patients, 2 patients had achieved complete response (CR) after 1 cycle of therapy (one patient had prior allogeneic HCT, CD7 CAR-T therapy and daratumumab) (Table 2). The two responders remain on treatment. Conclusions: XmAb18968, a novel CD-38 bispecific antibody appears safe and is showing response at the starting dose level in T-ALL. The study is currently enrolling additional patients with T-ALL. Updated analysis with additional patients and details on correlative studies examining mechanisms of therapeutic efficacy will be reported at the main meeting.

Transgenic Mouse Model for Translational Immunotherapy Studies on Multiple Myeloma

Background Genetically engineered mouse models that recapitulate key immunological features of human multiple myeloma may lend themselves to preclinical design and testing of novel immune therapies that target members of the tumor necrosis factor (TNF) receptor superfamily in addition to BCMA. One model of this sort are double-transgenic IL6Myc mice that spontaneously develop myeloma-like plasma cell tumors (PCTs) with full genetic penetrance (100% tumor incidence) and relatively short latency (4-5 months) in presence of an intact innate and adaptive immune system (Rutsch et. al. Blood 2010). IL6Myc mice exhibit serum M-spikes, respond to proteasome inhibition, and develop osteolytic lesions mimicking myeloma bone disease (Duncan K et. al. Blood Cancer J 2013, Sun F et. al. Haematologica 2020). Here, we examined changes in the immune tumor microenvironment during PCT progression in IL6Myc mice. We found that neoplastic plasma cell development was accompanied by accumulation of inhibitory T cells, T cell exhaustion, and elevated serum levels of MIP-3α and MCP-5. A subset of aberrant plasma cells expressed the TNF receptors, TACI and BAFF-R, which, together with their ligands, APRIL and BAFF, may serve as immunotherapeutic targets in myeloma not responding to BCMA-targeted treatment (Wong DP et. al. Nat Commun 2022, Braunstein M et. al. Expert Rev Hematol 2021). Materials and methods Double-transgenic IL6Myc mice were bred by intercrossing homozygous transgenic C.iMyc ΔEμ (Duncan K et. al. Blood Cancer J 2013) and heterozygous transgenic C.IL6 mice (Kovalchuk AL. et. al. Proc Natl Acad Sci USA 2002). Age-matched IL6Myc mice were investigated at an early (5-7 weeks), intermediate (10-12 weeks) and late (14-17 weeks) stage of PCT development using flow cytometry (Cytek Aurora) and serum cytokine levels (Bio-Plex) as main research tools. Results Bone marrow (BM) plasma cells, defined as CD45-gated B220 -CD138 + cells, increased during PCT development, as one might have expected: 10.5 ± 5.8% and 26.8 ± 6.4% ( p< 0.05) in early- and late-stage mice, respectively. The proportion of B220 +CD19 + B cells fell accordingly: 29.6 ± 4.1% vs 5.5 ± 4.9% ( p< 0.0001). Consistent with the notion that the BM microenvironment of PCT-bearing mice is immunosuppressive, there was a 2-fold elevation of TGF-β expressing T cells and a 4-fold elevation of IL-10 expressing T cells in the BM when late-stage mice were compared to early-stage mice. A sizeable fraction of aberrant plasma cells expressed TACI and BAFF-R in addition to BCMA ( Figure 1, left). Spleens of IL6Myc mice undergoing tumor development contained increasing numbers of FoxP3 + regulatory T cells (8.6 ± 2.1% at early stage vs 14.0 ± 4.6% at late stage, p< 0.05) and CD11b +Ly-6G/C + myeloid-derived suppressor cells (21.2 ± 9.2% vs 51.6 ± 10.1%, p< 0.01). Exhausted T cells, detected via expression of PD-1, TIM-3, LAG-3 and TIGIT, increased in sync with PCT progression ( Figure 1, right). Elevated serum levels of inflammatory cytokines, including MIP-3α (95.3 ± 41.9 pg/ml in early-stage mice vs 514 ± 279 pg/ml in late-stage mice, p< 0.01) and MCP-5 (121 ± 43.9 pg/ml vs 284 ± 70.5 pg/ml, p< 0.05), agreed with flow-based tissue data. Conclusion Neoplastic plasma cell development in IL6Myc mice takes place in an immune suppressed tumor microenvironment similar to that promoting human myeloma. IL6Myc-driven PCTs may provide a good experimental model system for novel immunotherapeutic approaches that target TACI and BAFF-R or their ligands, APRIL and BAFF. Previous work to that end holds great promise but has been challenging thus far (Goodman DB et. al. Sci Transl Med 2022, Lee L et. al. J Immunother Cancer 2023).

A Phase 1 Study of CD38-Bispecific Antibody (XmAb18968) for Patients with CD38 Expressing Relapsed/Refractory Acute Myeloid Leukemia

Background: Outcomes of adults with relapsed/refractory acute myeloid leukemia (RR-AML) have remained poor. CD38 is a transmembrane glycoprotein that is highly expressed in AML and is potentially targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We designed a phase I clinical trial to assess the safety and tolerability of XmAb18968 in patients with RR-AML. Methods: We conducted a multicenter, open label, phase I dose escalation study of XmAb18968 (NCT05038644). Patients aged ≥18 years with relapsed/refractory AML, ECOG PS 0-2 and adequate organ function were eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, active acute graft-versus-host disease, and acute promyelocytic leukemia. Dose escalation was conducted using 3+3 design and 4 separate dose levels were studied [0.8mg, 1mg, 1.3mg, 1.5mg]. XmAb18968 was administered intravenously on days 1, 8, 15, 22 on a 28-day cycle. During cycle 1 alone, day 1 dose was fractionated and administered over 2 days to minimize the risk of significant cytokine release syndrome (CRS). Treatment was continued until progression or unacceptable toxicity. The primary objective was to determine the safety and dose limiting toxicity (DLT) and secondary objective was to determine the preliminary efficacy. Measurable residual disease (MRD) status was assessed using multicolor flow cytometry with 0.01% sensitivity. Correlative studies included pharmacokinetics, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy, and direct glycopeptide analysis. Results: Thirteen patients with RR-AML were enrolled, 12 of whom were evaluable (1 patient came off study before DLT period). Median age was 63 years (45-77), 77% with adverse risk disease, 38% with secondary AML, and received median two (range 2-7) prior lines of therapy. Twelve of 13 patients (92%) were previously treated with venetoclax based regimen and 31% had prior allogeneic HCT. Adverse risk mutations included TP53 (31%), RUNX1 (23%), and ASXL1 (15%). Grade 3 or higher adverse events included anemia (8%), neutropenia (15%), and thrombocytopenia (23%) (Table 1). CRS grades 1-2 were noted in 62% of patients, no grade ≥3 CRS or neurotoxicity (any grade) was seen. There was no dose limiting toxicity (DLT). Of the 12 evaluable total patients, clinically meaningful response was noted in two patients who were MRD positive by flow cytometry prior to study entry and achieved MRD negative CR (Table 2). These two patients who achieved MRD negative CR subsequently proceeded to allogeneic HCT. Median time to response was 1 cycle. Median OS of the cohort was 6.2 months (1.8-NR). Conclusions: XmAb18968 is safe and well tolerated in patients with RR-AML. Dose escalation yielded MRD negative CR in RR-AML patients who were MRD positive at study entry. Details on correlative studies examining mechanisms of therapeutic efficacy and resistance will be reported in the main meeting.

P55 Real-world clinical and patient-reported outcomes of talimogene laherparepvec (T-VEC) treatment for melanoma in transit and nodal metastases at a UK centre

Abstract Talimogene laherparepvec (T-VEC) is a National Institute for Health and Care Excellence-approved oncolytic viral intralesional immunotherapy licensed for unresectable stage III(B)–IV(M1a) melanoma. It is a genetically modified herpes simplex virus that selectively replicates in tumour cells, leading to local and systemic antitumour immune responses, improving overall survival. The randomized phase III OPTiM trial reported a complete response in 28.2% of patients (Andtbacka RH, Collichio F, Harrington KJ et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec vs. granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV melanoma. J Immunother Cancer 2019; 7:145). We report a retrospective review of clinical and patient-reported outcomes of a dermatology-led T-VEC service at a regional UK melanoma centre between January 2019 and January 2023. Treatment involves a loading dose and then two-weekly nurse-delivered intralesional injections. Patient demographics, clinical characteristics, toxicities, treatment responses and patient satisfaction were recorded. Sixteen patients (11 women and five men) were treated; the average patient age was 73 years (range 42–87). Seven patients had stage IIIB disease, six stage IIIC and three stage IVM1a. Eight had received prior nonsurgical treatments (adjuvant therapy, electrochemotherapy, diphencyprone). The number of lesions treated per visit ranged from 1 to 24 (median 5) over a median of six visits (range 2–24). Four patients (25%) had a complete response (CR), with median time to CR being 8 weeks; all have maintained the response (range 6–45 months). Eight (50%) showed partial response (PR), with three continuing treatment. Nine patients overall had progressive disease (five in the PR group and four who were nonresponders). In total, five patients died. Patients experienced mainly flu-like symptoms (44%), pyrexia (31%), fatigue (19%), muscle pain (19%), nausea (19%), headache (19%), diarrhoea (6%), joint pain (6%), local swelling (19%), lymphadenopathy (6%) and mild pain (25%). No grade 3 or 4 toxicity occurred. A patient satisfaction questionnaire was returned by seven of eight patients who completed treatment. All said they received adequate information to make treatment decisions. Eighty-six per cent rated the service excellent. Our results show comparable efficacy and side-effects to published clinical trials and demonstrate that T-VEC is a well-tolerated and safe treatment option, delaying or potentially avoiding need for more toxic systemic agents. We highlight that dermatologists and nurse specialists are well placed to deliver T-VEC in patients with melanoma.

A phase II trial with copanlisib plus avelumab as maintenance therapy for metastatic bladder cancer after platinum-based chemotherapy.

TPS4610 Background: Bladder cancer is the tenth most common malignancy and the fourteenth most common cause of cancer death worldwide. Currently, platinum-based chemotherapy followed by avelumab maintenance immunotherapy is the first-line standard of care for advanced bladder cancer (aBC). Even though maintenance avelumab therapy has improved overall survival, its efficacy is still disappointing with a response rate of less than 10% and progression-free survival benefit of 1.7 months. The phosphoinositide 3-kinase (PI3K) pathway harbors more activating alterations than any other growth signaling pathway in aBC. Furthermore, PI3K δ and γ are expressed by immune cells and regulate their function. Activation alterations along the PI3K pathway are putative molecular drivers and can possibly be targeted for the treatment of aBC. In preclinical studies, we found that a pan-PI3K class I inhibitor, copanlisib, potentiates anti-programmed cell death 1 (PD1) antibody in syngeneic bladder cancer mouse models with or without activation alterations along the PI3K pathway (Zhu S, J Immunother Cancer. 2021). We hypothesize that copanlisib potentiates avelumab as maintenance therapy for aBC. Methods: This is a multi-center, single-arm, open-label Phase II trial with a lead-in safety phase to determine the efficacy and toxicity of combination copanlisib and avelumab maintenance therapy in aBC. The major inclusion criteria are patients with aBC without disease progression after platinum-based chemotherapy and no contraindication for avelumab and copanlisib. With a type I error of 5% and power of 80% with a log-rank test, we will need 26 patients for this study. With an attrition rate of 10%, we will enroll 29 patients from four US Department of Veterans Affairs Medical Centers. Copanlisib will be administered through intravenous infusion (IV) at 60 mg on Day 1, 8 and 15, and avelumab will be administered 800 mg IV on Day 1 and 15 of each 4-week treatment cycle for up to 26 cycles. Imaging will be repeated every two cycles during first year of therapy and thereafter every 3 cycles or clinically indicated. The primary endpoint is progression-free survival (PFS). The secondary endpoints include CT or MRI determined radiographic overall response rate, toxicity, overall survival, and molecular correlative studies. Kaplan-Meier estimates will be presented together with median PFS with 2-sided 95% confidence intervals (CI). In particular, the PFS rates at 3, 6, 9, 12 and 15 months will be estimated with corresponding 2-sided 95% CIs. Adverse events will be assessed according to CTCAE v5. Tumor response is determined according to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 criteria. This study is currently open for enrollment. Clinical trial information: NCT05687721 .

Phase 2 study of ISA101b (peltopepimut-S) and cemiplimab in patients with advanced HPV16+ oropharyngeal cancer who failed anti-PD1 therapy.

6028 Background: ISA101b (peltopepimut-S), a therapeutic vaccine against the HPV-specific E6/E7 oncoproteins, induces specific expansion of HPV16 targeted T-cells when given together with cemiplimab, an anti-PD-1 agent. Previously we showed that ISA101 with nivolumab achieved a higher response rate compared to immune checkpoint inhibitor (ICI) alone in trials for patients with recurrent/metastatic (R/M) HPV16+ oropharyngeal cancer (OPC)1,2. Methods: In this single arm phase 2 study, patients with R/M HPV16+ OPC with progressive disease (PD) within 6 months after prior 1st or 2nd line anti-PD-1 ICI were treated with ISA101b (subcutaneously 100µg/peptide on days 1, 29, and 50) with cemiplimab (intravenously 350mg as a 3-weekly regimen) until PD. Patients without PD at 6 months were offered a booster ISA101b injection. HPV16 positive tumor status was confirmed by a central reference laboratory with an established PCR assay. The primary efficacy endpoint was defined as overall response rate (ORR) as per RECIST1.1. An analysis was planned at the end of Stage 1, when 26 patients who had received at least one dose of ISA101b had been followed for 6 months. The cut-off date for this analysis, approved by the DSMB, was 31 January 2023. Results: Twenty-six patients (mean age 60.7 ±12.9 years; 22 (84.6%) male and 4 (15.4%) female) enrolled in Stage 1. Median follow-up was 16.2 weeks (range 1.6-78.8). Three patients were confirmed with partial response (PR) (11.5%); two of the 3 patients with PR never responded to previous ICI treatment. In 13 patients (50.0%) best overall response (BOR) was stable disease (SD); in 8 patients (30.8%) BOR was PD. Two (7.7%) patients did not have a tumor assessment after baseline: one patient died on day 8 due to OPC and one patient withdrew consent shortly after enrolment. The clinical benefit ratio (CBR) was 61.5%. Nine (34.6%) patients received a booster injection. At the time of the booster, 2 patients had PR and 5 patients had meaningful (≥6 months) SD. Time to response ranged between 127 and 307 days. Median duration of study treatment was 13.1 weeks (range 1.1-75.9), with 4 patients still on treatment. There were two grade 3 adverse events (AEs) related to ISA101b: erythema at the injection site and diarrhea. Two patients (7.7%) had grade 3 ICI-related auto-immune events. Grade 4-5 AEs related to study treatment did not occur. Median overall survival was 8.1 months (range 0.3-17.5). Conclusions: This treatment appears promising for HPV16+ OPC patients who failed prior anti-PD-1 ICI therapy, with an ORR of 11.5% and a CBR of 61.5%. In this small, ongoing study the combination of cemiplimab and ISA101b was well tolerated with a safety profile resembling anti-PD-1 monotherapy. This is the first study of the combination of ISA101b and cemiplimab in 2nd/3rd line R/M anti-PD-1 refractory OPC patients. 1Massarelli E. JAMA Oncol 2019 2de Sousa LG. J Immunother Cancer 2022. Clinical trial information: NCT04398524 .

Abstract 3001: Investigating the quantity and quality of dendritic cells in human glioblastoma tissues and in orthotopic murine xenograft and syngraft models of glioblastoma

Abstract WHO grade 4 glioblastoma multiforme (GBM) has a very poor prognosis even after standard treatment with surgery, radiotherapy, and chemotherapy. Tumor recurrence is virtually inevitable when it is fatal. Chimeric Antigen Receptor (CAR)-T cell therapy is a promising new modality of therapy for GBM patients. Even though second-generation CAR-T cells may be considered to operate autonomously because co-stimulation is inherent to CAR design, the tumor microenvironment of GBM is particularly hostile to immune cells and their normal functions. In our recently published work (Gargett et al. J Immunother Cancer 2022; 10(9): e005187), CAR-T cells specific for the glioblastoma antigen, GD2, had improved antitumor activity if the CAR-T cells co-expressed IL-15. Although IL-15 co-expression prolonged control of intracranial tumor xenografts, tumors escaped immune control in most cases. Our early data suggest that a relative lack of intratumoral dendritic cells (DCs) may be a contributory factor. DCs are central to the initiation and maintenance of adaptive immune responses. Hence, we were interested to survey and characterize the DC content of glioblastoma tissues obtained either from human surgical samples or mice bearing orthotopic xenografts and syngrafts. We have used multi-colour flow cytometry to enumerate and evaluate the maturation status of subsets of DCs together with other types of immune cells among single cell suspensions of isolated glioblastoma tissues. Our preliminary findings are: Total DCs (mean +/- SD), which were defined as lineage-negative and HLA-DR (+), were significantly reduced among total viable cells of glioblastoma tissues (0.845% +/- 0.569) and peripheral blood mononuclear cells (PBMCs) (0.755% +/- 0.601) from GBM patients (n=12) compared to PBMCs (1.77% +/- 0.611) from healthy donors (n=12).No significant differences were detected in the percentages of total DCs among splenocytes of nontumor-bearing C57BL/6 (B6) mice (n=6) compared to B6 bearing othotopic syngrafts of the GL261 (n=3) or C2TA (n=3) glioblastoma cell lines. We will present more detailed analyses from human glioblastoma samples. In addition, we will present a more extensive characterization of DCs from the orthotopic murine models of glioblastoma: we will compare DCs and other types of immune cells in tumor and in the primary and secondary lymphoid tissues of both tumor-bearing and nontumor-bearing mice. We expect that the final data will fill a current gap in knowledge and indicate possible therapeutic strategies that might correct for the quantitative and qualitative defects in dendritic cells in glioblastoma. We hypothesize that adequate correction of these defects in vivo may augment the anti-glioblastoma activity of CAR-T cell therapies. Citation Format: Michael P. Brown, Tessa Gargett, Bryan J. Gardam. Investigating the quantity and quality of dendritic cells in human glioblastoma tissues and in orthotopic murine xenograft and syngraft models of glioblastoma [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 3001.

Abstract 1870: VBI-003, a CD47xEpCAM bispecific antibody as a potential treatment for colorectal and small cell lung cancers

Abstract CD47/SIRPα axis is an important checkpoint of innate immune system and is often exploited by tumor cells to evade host immune surveillance. In recent years, therapies such as anti-CD47 monoclonal antibodies (mAbs) and SIRPα fusion proteins that target this axis have garnered much attention. Although exciting clinical activities have been observed in hematological cancers, responses in solid tumors are less impressive and often require complex combination strategies. We previously described a novel CD47xEpCAM bispecific antibody, VBI-003, built on a human IgG1 backbone to harness the power of blocking CD47/SIRPα pathway while preserving the effector functions of IgG1 Fc (J ImmunoTher Cancer 2021;9:doi: 10.1136/jitc-2021-SITC2021.274). The bispecific design aims to improve selectivity so that SIRPα blocking and stable binding occur selectively on tumor cells where both CD47 and EpCAM are present. In vitro studies show that VBI-003 exhibits minimal red blood cell binding and does not cause hemagglutination, in contrast to benchmark CD47 mAb. VBI-003 has potent single agent activity in cell line derived xenograft (CDX) models of gastric and esophageal cancers. Here, we further explored the anti-tumor activities of VBI-003 in areas with great unmet needs such as small cell lung cancers (SCLC) and colorectal cancers (CRC). Gene expression analysis from public datasets reveals frequent expression of CD47 and EpCAM in SCLC and CRC tumors. Flow cytometry studies confirmed co-expression of CD47 and EpCAM on SCLC and CRC cell lines. Furthermore, in vitro assays showed that VBI-003 has potent EpCAM dependent SIRPα blocking, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity activities towards SCLC and CRC cell lines. Moreover, VBI-003 demonstrated potent single agent activity in multiple CDX models of SCLC with tumor regression and often outperformed benchmark CD47 mAb. Significant tumor growth inhibition was observed in colorectal cancer models post VBI-003 treatment, with additional activity by combination with standard of care chemotherapies. VBI-003 synergized with irinotecan and outperformed monotherapy groups in CDX models of CRC. In conclusion, VBI-003 has potent single agent activity in SCLC tumor models and combined synergistically with irinotecan in CRC models. Our data support further investigation of VBI-003 as a treatment for CD47 and EpCAM expressing SCLC and CRC. Citation Format: Oi Kwan Wong, Xinhua Wang, Xiaocheng Chen, Leonard Post. VBI-003, a CD47xEpCAM bispecific antibody as a potential treatment for colorectal and small cell lung cancers [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 1870.

Disease Etiology and Outcomes After Atezolizumab Plus Bevacizumab in Hepatocellular Carcinoma: Post-Hoc Analysis of IMbrave150

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC) by inducing meaningful rates of antitumor responses and having favorable toxicity profiles. Based on large, randomized phase III trials, including the IMbrave150 study testing atezolizumab plus bevacizumab vs sorafenib, combination ICI regimens have emerged as the preferred frontline treatments for HCC based on their overall survival (OS) benefit. 1 Finn R.S. et al. N Engl J Med. 2020; 382: 1894-1905 Crossref PubMed Scopus (2345) Google Scholar ,2 Abou-Alfa G.K. et al. N Engl J Med. 2022; 1 Google Scholar HCC biology may be influenced by distinct etiologies underlying tumorigenesis including viral infections, alcohol-related injury, and metabolic causes. Based on in vivo models and retrospective studies, nonalcoholic fatty liver disease (NAFLD)-related HCC is purported to be resistant to ICIs. 3 Pfister D. et al. Nature. 2021; 592: 450-456 Crossref PubMed Scopus (345) Google Scholar , 4 Heinrich B. et al. Gastroenterology. 2021; 160: 331-345 Abstract Full Text Full Text PDF PubMed Google Scholar , 5 Foerster F. et al. Hepatology. 2022; 75: 1604-1626 Crossref Scopus (21) Google Scholar , 6 Kelley R.K. et al. N Engl J Med. 2021; 385: 280-282 Crossref PubMed Scopus (0) Google Scholar , 7 Haber P.K. et al. Gastroenterology. 2021; 161: 879-898 Abstract Full Text Full Text PDF PubMed Google Scholar Despite their limitations, these lines of evidence have led to the prevailing notion that the underlying etiology of liver disease influences ICI outcomes in HCC, with NASH being a barrier to ICI benefits, although this finding remains controversial. 5 Foerster F. et al. Hepatology. 2022; 75: 1604-1626 Crossref Scopus (21) Google Scholar , 6 Kelley R.K. et al. N Engl J Med. 2021; 385: 280-282 Crossref PubMed Scopus (0) Google Scholar , 7 Haber P.K. et al. Gastroenterology. 2021; 161: 879-898 Abstract Full Text Full Text PDF PubMed Google Scholar , 8 Ho W.J. et al. J Immunother Cancer. 2020; 8 Google Scholar Herein, we performed a post-hoc patient-level analysis of the IMbrave150 trial to evaluate if cirrhosis etiology affects survival or antitumor responses after atezolizumab plus bevacizumab.

Characterization of Patients With Metastatic Renal Cell Carcinoma Experiencing Complete Response to First-line Therapies: Results From the International Metastatic Renal Cell Carcinoma Database Consortium.

Clinical trials have demonstrated higher complete response rates in the immuno-oncology-based combination arms than in the tyrosine kinase inhibitor arms in patients with metastatic renal cell carcinoma. We aimed to characterize real-world patients who experienced complete response to the contemporary first-line therapies. Using the International Metastatic Renal Cell Carcinoma Database Consortium, response-evaluable patients who received frontline immuno-oncology-based combination therapy or tyrosine kinase inhibitor monotherapy were analyzed. Baseline characteristics of patients and post-landmark overall survival were compared based on best overall response, as per RECIST 1.1. A total of 52 (4.6%) of 1,126 and 223 (3.0%) of 7,557 patients experienced complete response to immuno-oncology-based and tyrosine kinase inhibitor therapies, respectively (P = .005). An adjusted odds ratio for complete response achieved by immuno-oncology-based combination therapy (vs tyrosine kinase inhibitor monotherapy) was 1.56 (95% CI 1.11-2.17; P = .009). Among patients who experienced complete response, the immuno-oncology-based cohort had a higher proportion of non-clear cell histology (15.9% and 4.7%; P = .016), sarcomatoid dedifferentiation (29.8% and 13.5%; P = .014), and multiple sites of metastases (80.4% and 50.0%; P < .001) than the tyrosine kinase inhibitor cohort. Complete response was independently associated with post-landmark overall survival benefit in both the immuno-oncology-based and tyrosine kinase inhibitor cohorts, giving respective adjusted hazard ratios of 0.17 (95% CI 0.04-0.72; P = .016) and 0.28 (95% CI 0.21-0.38; P < .001). The complete response rate was not as high in the real-world population as in the clinical trial population. Among those who experienced complete response, several adverse clinicopathological features were more frequently observed in the immuno-oncology-based cohort than in the tyrosine kinase inhibitor cohort. Complete response was an indicator of favorable overall survival.

Abstract IA019: Molecular pathological epidemiology of tumor microbiota and immunity can give etiologic insights

Abstract This lecture discusses the integration of tumor microbiology and immunology into evolving/expanding molecular pathological epidemiology (MPE) research framework (Ogino et al. Gut 2011; Ogino et al. Annu Rev Pathol 2019; Inamura et al. Gut 2022; etc.), which will open new opportunities. Neoplasms represent heterogeneous pathological processes due to interactive influences of the exposome (including the microbiome), the immune system, and neoplastic cells. Hence cancers should be regarded as not only microenvironmental diseases but also environmental and systemic diseases (Inamura et al. Gut 2022). To address this complexity, we investigate influences of exposures on microbial-tumor-immune interactions in tumor microenvironment. Colorectal cancer (CRC) provides an ideal model, as the colorectum is the most microbial rich organ and there are many established or putative risk factors for CRC. In our proof-of-principle studies that used the Nurses’ Health Study and Health Professionals Follow-up Study along with tumor tissue biobanks having 1700 CRC cases, we can provide evidence for influences of prudent diets (Mehta et al. JAMA Oncol 2017), inflammatory diets (Liu et al. Clin Gastroenterol Hepatol 2018), and western diets (Arima et al. Gastroenterology 2022) on developments of cancer subtypes with intratumor bacteria such as Fusobacterium nucleatum and pks+ Escherichia coli. We have also gain insights into interactions between microbes and immune cells. We have discovered an inverse relationship between F. nucleatum and T cell infiltrates (Mima et al. JAMA Oncol 2015), especially CD3+CD4+CD45RO+ memory helper T cells (Borowsky et al. Clin Cancer Res 2021). In situ spatial single cell analyses using multispectral fluorescence imaging and machine learning can shed light on the roles of microbes as well as various immune cell infiltrates in CRC (Vayrynen et al. Cancer Immunol Res 2021; Vayrynen et al. J. ImmunoTher Cancer 2021; Vayrynen et al. Cancer Immunol Res 2022; Akimoto et al. Front Immunol 2022). The integrative MPE approach is also expected to advance research on early-onset cancers (Akimoto et al. Nat Rev Clin Oncol 2021; Ugai et al. Nat Rev Clin Oncol, in press). Our new research paradigm to integrate microbial and immune assays on archival tumor tissue in large-scale population studies can provide not only etiological insights but also possible paths for precision medicine and prevention. Citation Format: Shuji Ogino. Molecular pathological epidemiology of tumor microbiota and immunity can give etiologic insights [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA019.

Plasma Exchange for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitor Therapy: Implications for Clinical Care and Clinical Trial Design

Therapeutic plasma exchange (TPE) is increasingly utilized for Grade 3-4 immunotherapy adverse events (irAEs) to accelerate elimination of drug, autoantibodies, and cytokines. Immune checkpoint inhibitors (ICI) are IgG1 or IgG4 constructs with long half-lives (t1/2) and volume of distributions (Vd) favorable for clearance by apheresis. As drug levels are not readily available, the number of sessions needed to eliminate ICIs is estimated based on the interval from last drug dose, drug Vd, and drug t1/2. Increased use of TPE is anticipated as ICIs are now given despite preexisting autoimmunity, prior organ transplantation, and/or prior irAEs. TPE protocols are well established for the management of diseases that can also present as irAEs [e.g. thrombotic thrombocytopenic purpura (TTP), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), hemophagocytic lymphohistiocytosis (HLH)] and for drug removal (e.g. natalizumab). While TPE is included in irAE management guidelines as second line therapy or later (Brahmer JR, et al, J Immunother Cancer, 2021 PMID: 34172516), no randomized controlled trial (RCT) data are available. TPE can reduce the level of clinical biomarkers for irAE monitoring: creatinine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT),fibrinogen, platelet count, ferritin. We treated 4 adults (median age 66 years, range 65-77 years) with TPE for steroid-refractory irAEs [myositis (2), myocarditis (1)] and, as part of initial therapy, in combination with dexamethasone and anakinra, for ICI-associated HLH. ICI constructs were IgG1 anti-PD-L1 (envafolimab, durvalumab) and IgG4 anti-PD-1 (nivolumab, cemiplimab). Data collection was IRB approved and with patient written consent. ICI indications were sarcoma, thymic carcinoma, cutaneous squamous cell carcinoma (SCC), and lung SCC. Only one patient (HLH irAE) had preexisting autoimmunity (thyroiditis). Median time from last ICI dose to first irAE symptoms or signs was 16 days (range 5-29 days). Three of 4 patients developed irAE after the first ICI dose. One patient (myocarditis) required full systemic anticoagulation (heparin, then enoxaparin) for atrial fibrillation and deep venous thrombosis, and dual antiplatelet therapy (DAPT) for a new coronary stent. The two myositis patients received prophylactic enoxaparin. All TPE sessions were one plasma volume exchange through central venous access, utilized Anticoagulant Citrate Dextrose Solution A (ACDA), and scheduled daily or every other day. Number of sessions ranged from 2-4. Except for the patient with HLH, TPE was initiated with 5% albumin replacement. Fibrinogen levels and estimated bleeding risk guided the need for fresh frozen plasma (FFP) replacement. Session intervals, exchange fluid, transfusion, biomarkers, changes in fibrinogen and platelet count, anticoagulation, and functional response are detailed in Table 1. Three of 4 patients, who had normal baseline fibrinogen and platelet counts, experienced clinically significant hypofibrinogenemia resulting in discontinuation of chemical DVT prophylaxis and/or cryoprecipitate transfusion, but did not have clinically significant thrombocytopenia. The fourth patient (HLH) required ongoing transfusion support due to pre-TPE hypofibrinogenemia and thrombocytopenia. TPE confounded interpretation of biomarkers in all. All irAEs demonstrated prompt clinical improvement, however, due to rapid corticosteroid tapers, 2 patients (myositis, HLH) relapsed within 1 month from last TPE. Both responded to additional immunosuppression. One patient (myositis) did not relapse. Grade 4 bleeding occurred in the patient receiving enoxaparin and DAPT and led to discontinuation of TPE after 2 sessions. Our experience supports the following when considering TPE for irAEs: 1) exclusion of patients with high bleeding risk, or use of 100% FFP replacement and every other day TPE; 2) meticulous non-biomarker irAE assessment during and after TPE; 3) RCT design includes irAE relapse timing and rates and long term follow-up to assess cumulative immunosuppression and tumor outcome; 4) serial drug levels and correlative studies (e.g. cytokines, autoantibodies) to better understand TPE mechanisms, persistence of irAEs, and long term ICI anti-tumor benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

First in Human Clinical Responses and Persistence Data on TEG001: A Next Generation of Engineered Αβ T Cells Targeting AML and MM with a High Affinity γ9δ2TCR

Introduction: γδT cells target malignant cells by sensing cancer mediated metabolic changes via their γδTCR[1]. We have developed the TEG001 cell product as an 'academic in house product', which are αβ T cells expressing the high affinity Vγ9Vδ2 TCR clone 5 [2]. TEG001 showed tumor reactivity towards a range of malignant cell lines, primary material from patients with various hematological malignancies as well as efficacy in murine models[3]. Here we present the results of dose level 1 and 2, addressing the safety and tolerability of TEG001 in patients with acute myeloid leukemia (AML) or multiple myeloma (MM) (NL6357). Methods: The TEG001 study (NL6357), is a single center, investigator-initiated study, with a standard 3+3 dose escalation design. Cohorts receive a single infusion of 1x106 TEG001 cells/kg (dose level 1), 3x106 TEG001 cells/kg (dose level 2) and 1x107 TEG001 cells/kg (dose level 3). Relapsed and/or refractory AML/high risk MDS and MM patients were eligible. AML patients with > 30% blasts or circulating blasts required bridging therapy. TEG001 cells were produced as previously described[2]. The conditioning regimen consisted of fludarabine i.v. 25 mg/m2 (day -4 to -2) and cyclophosphamide i.v. 900 mg/m2 (day -2). Pamidronate (PAM) (30 mg I.V.) was administered on day 0 and on day 28 to propagate TEG001 activity. TEG001 is detected in peripheral blood samples by flow cytometry as part of immune monitoring (details in Fig. 2). The primary endpoint was the development of dose-limiting toxicities (DLTs) in order to determine the maximum tolerated dose. Main criteria for reaching DLTs were TEG001 related adverse events (AEs) requiring ventilator support and grade 4 AEs not related to the underlying disease. AEs contributable to cytokine release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (iCANS) grade 3 responding to tocilizumab and/or steroids were not defined as a DLT. Results: Fourteen patients were included. Of the six patients that were not infused, three patients did not respond to bridging chemotherapy, for two patients TEG001 product could not be manufactured for the intended target dose level and one patients went off study due to COVID-19 induced hospital restrictions. Eight patients were dosed: three patients in dose level 1 and three patients in dose level 2. Two patients received an 'out of specification' dose (77% of dose level 1; and 36% of dose level 2, respectively). Of the six patients infused in dose level 1 and 2, five patients had AML and one patient had MM (Fig. 1). No DLTs were observed. No AEs > grade 3 related to TEG001 were observed. Patient 16 (dose level 2), who received PAM according to the protocol on day 0 and 28, developed 2 seizures at day 29 and 30. The seizure responded well to levetiracetam and no other neurological signs associated with iCANS were observed. No infections or abnormalities in the spinal fluid or brain imaging were identified and connection of the seizure to TEG001 remained inconclusive. In all patients TEG001 cells were detectable in peripheral blood by flowcytometry (dose level 2 depicted in Fig. 2). In dose level 1, patient 7 had stable disease (SD, duration 3M). In dose level 2, patient 9 had a blast reduction (not meeting criteria for partial remission (PR); duration 12M) and patient 16, who had 28% bone marrow blasts prior to TEG001 infusion showed full hematological recovery (Fig. 2) and achieved a complete remission (CR, duration 6M). Conclusion: TEG001 cells are well-tolerated at the first 2 dose levels tested. TEG001 cells show persistence up to day 56. One out of three AML patients in dose level 2 achieved a CR one month after TEG001 infusion and SD was observed in both dose levels. The TEG001 study is currently recruiting patients for dose level 3 (1x107 cells/kg). This study was financially supported by Gadeta b.v. [1] Sebestyen, Z., et al., Translating gammadelta (gammadelta) T cells and their receptors into cancer cell therapies. Nat Rev Drug Discov, 2019. [2] Straetemans, T., et al., GMP-Grade Manufacturing of T Cells Engineered to Express a Defined gammadeltaTCR. Front Immunol, 2018. 9: p. 1062 [3] Johanna, I., et al., Evaluating in vivo efficacy - toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells. J Immunother Cancer, 2019. 7(1): p. 69. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract CT119: A randomized, double-blind phase 2 evaluation of the anti-IL-8 monoclonal antibody BMS-986253 + nivolumab + ipilimumab vs nivolumab + ipilimumab in patients with advanced melanoma that progressed on/after anti-PD-(L)1 therapy

Abstract Purpose: This phase 1/2 trial evaluates the novel immunotherapy BMS-986253 in combination with immune checkpoint inhibitors (NCT03400332). Interleukin-8 (IL-8) is an immunosuppressive chemokine often elevated in the serum of patients with cancer. High serum IL-8 concentration is associated with poor prognoses and resistance to immunotherapies, including anti-programmed death-1 (PD-1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents (Schalper et al. Nat Med 2020;26:688). The addition of anti-IL-8 therapy to anti-PD-1 nivolumab (NIVO) and anti-CTLA-4 ipilimumab (IPI) may sensitize patients with high serum IL-8 levels to immune checkpoint inhibition. BMS-986253, a fully human IgG1 anti-IL-8 monoclonal antibody, in combination with NIVO ± IPI is under investigation in a phase 1/2 trial of patients with advanced solid tumors. Initial results from part 1 indicate BMS-986253 + NIVO was well tolerated with no dose-limiting toxicities (Davar et al. J Immunother Cancer 2020;8. Abstract 394). Preliminary antitumor activity was observed, including partial responses in 5 of 28 patients with melanoma that had progressed on or after prior anti-PD-(L)1 therapy, a population with high unmet medical need. Part 2 is a randomized, double-blind phase 2 study comparing the efficacy of BMS-986253 in combination with NIVO + IPI vs NIVO + IPI in patients with advanced melanoma that progressed on or after prior anti-PD-(L)1 therapy. Trial Design: Patients eligible for part 2 have histologically confirmed, unresectable, stage III/IV melanoma, have progressed on or after anti-PD-(L)1 treatment, had an anti-PD-(L)1 agent as their most recent therapy, and have not received anti-CTLA-4 treatment. PD-L1 and BRAFV600 mutation status (wild-type and BRAF mutations permitted) must be documented, and serum IL-8 levels will be measured at screening. Patients will be randomized 1:1 to receive BMS-986253 + NIVO + IPI or placebo + NIVO + IPI and stratified by serum IL-8 level, BRAF V600E status, and lactate dehydrogenase level. The dose and frequency of BMS-986253, NIVO, and IPI will be determined by part 1 data. Treatment with BMS-986253 or placebo and NIVO will continue ≤ 3 years or until disease progression or intolerance. The primary objective is to compare progression-free survival (PFS) by blinded independent central review (BICR) per RECIST v1.1 between treatment arms in patients with baseline serum IL-8 levels &amp;gt; 10 pg/mL. Secondary objectives include PFS by BICR in all randomized patients, overall response rates by BICR per RECIST v1.1, overall survival, safety, pharmacokinetic profile, immunogenicity of BMS-986253, and associations of baseline factors with response. Recruitment will continue until ≈170 patients are enrolled. Citation Format: Matteo Simonelli, Emiliano Calvo, Diwakar Davar, Jason Melear, Donald Richards, Matthew Dallos, Martin Gutierrez, Victor Moreno, Thomas Marron, Sylvie Rottey, Angela Orcurto, Susana Barriga, Jessy Fan, Elizabeth Gibson, Santanu Dutta, Vivek Arora, Ignacio Melero. A randomized, double-blind phase 2 evaluation of the anti-IL-8 monoclonal antibody BMS-986253 + nivolumab + ipilimumab vs nivolumab + ipilimumab in patients with advanced melanoma that progressed on/after anti-PD-(L)1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT119.

Abstract 5631: Immunomodulatory activity of sulindac plus erlotinib for colon cancer prevention in familial adenomatous polyposis

Abstract Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutation in Adenomatous Polyposis Coli (APC)1. Patients with FAP have a nearly 100% lifetime risk of colorectal cancer (CRC) due to the formation of hundreds to thousands of adenomatous polyps in the gastrointestinal tract2. A clinical trial in FAP patients demonstrated that Cox-1/2 inhibitor sulindac (SUL) plus EGFR inhibitor erlotinib (ERL) reduced polyp burden significantly in the colon and small intestine (SI), but toxicity issues raised concerns for durable long-term CRC interception3. In the Apc-mutant polyposis in rat colon (Pirc) rat model of FAP, we determined low-dose regimens of ERL+SUL that were both safe and efficacious4. In the current investigation, the lowest tested dose of dietary SUL (125 ppm continuously) plus ERL (5 mg/kg twice weekly), given at one-half the SUL clinical dose and one-fourth of the ERL clinical dose, administered for 46 weeks respectively, demonstrated good inhibition of tumor burden in the colon (&amp;gt;85% efficacy, p&amp;lt;0.05) and SI (&amp;gt;94% efficacy, p&amp;lt;0.05) compared to untreated controls. Moreover, treatment normalized organ weights and hematocrits that were altered in the untreated AIN controls.Recently, ERL5 and SUL6 were individually demonstrated to increase the recruitment of inflammatory immune cells in mouse models of lung and colon cancer, respectively. However, ERL+SUL in combination was not investigated in the context of immune cell infiltration and polarization. Our preliminary IHC data in the Pirc model indicated increased recruitment of CD8+ T cells in colon polyps by SUL 250 ppm + ERL 42 mg/kg once a week. RT-qPCR and immunoblotting analysis of colon polyps obtained from the low-dose combination of SUL 125 ppm + ERL 5 mg/kg twice weekly demonstrated increased CD4 expression and concurrently decreased oncogenic IL-17 expression and tumor associated macrophage markers (CD163 and CD206) (P&amp;lt;0.05 vs control). Additional immune markers will be identified and validated via CyTOF. We hypothesize that low-dose combination of SUL+ERL can enhance the recruitment of immune cells into early adenomatous colon and SI polyps, providing an effective immunointerception strategy, with potential clinical relevance for FAP patients before or after colectomy. Acknowledgements Research supported by NCI Contract Number 75N91019D00021, Task Order 75N91019F00130. 1.Groden J et al., Cell 1991; 66:589-600.2.Jasperson KW et al., Gastroenterology 2010; 138:2044-2058.3.Samadder NJ et. al., JAMA 2016; 315:1266-75.4.Ulusan AM et. al., Cancer Prev Res (Phila). 2021; 14:325-336.5.Ayeni D et al., J Immunother Cancer 2019; 7:172.6.Yi B et al., Mol Cancer Ther 2021; Apr 20. Citation Format: Chakrapani Tripathi, Roderick H. Dashwood. Immunomodulatory activity of sulindac plus erlotinib for colon cancer prevention in familial adenomatous polyposis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5631.