scholarly journals GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors

2021 ◽  
Vol 9 (8) ◽  
pp. e003005
Author(s):  
David G DeNardo ◽  
Anna Galkin ◽  
Jakob Dupont ◽  
Lei Zhou ◽  
Johanna Bendell
Keyword(s):  
Clinical Study ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Neutrophil Migration ◽  
Suppressor Cells ◽  
Special Focus ◽  
Preclinical Studies ◽  
Salt Form ◽  
Inflammatory Conditions ◽  
Tumor Types

Resistance to immune checkpoint inhibitors (ICI) and other anticancer therapies is often associated with the accumulation of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Therefore, targeting MDSC recruitment or function is of significant interest as a strategy to treat patients with ICI-resistant cancer. The migration and recruitment of MDSCs to the TME is mediated in part by the CD11b/CD18 integrin heterodimer (Mac-1; αMβ2), expressed on both MDSCs and TAMs. However, inhibition or blockade of CD11b/CD18 has had limited success in clinical trials to date, likely since saturation of CD11b requires doses that are not clinically tolerable with the agents tested so far. Interestingly, activation of CD11b with leukadherin-1 was found to reduce macrophage and neutrophil migration in animal models of inflammatory conditions. Preclinical studies with GB1275, a salt form of leukadherin-1, demonstrated that activation of CD11b improves the antitumor immune response and enhances the response to immunotherapy in mouse models of pancreatic adenocarcinoma, breast cancer and lung cancer. Based on the promising results from preclinical studies, a phase 1/2 clinical study (NCT04060342) of GB1275 in patients with advanced solid tumor types known to be resistant or less likely responsive to immuno-oncology therapies, including pancreatic, breast, prostate, and microsatellite-stable colorectal cancer, is ongoing. In this review, we examine targeting MDSCs as a therapeutic approach in cancer therapy, with a special focus on GB1275 preclinical studies laying the rationale for the phase 1/2 clinical study.

scholarly journals 317 A phase 1/1b study of SBT6050, a HER2-directed monoclonal antibody conjugated to a toll-like receptor 8 agonist, in subjects with advanced HER2-expressing solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A343-A343
Author(s):  
Leisha Emens ◽  
Muralidhar Beeram ◽  
Erika Hamilton ◽  
Sarina Piha-Paul ◽  
Valerie Odegard ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Myeloid Cells ◽  
Preclinical Studies ◽  
Her2 Expression ◽  
Toll Like Receptor

BackgroundNew strategies are needed to improve outcomes in human epidermal growth factor receptor 2 (HER2)-expressing cancers. SBT6050 is a novel therapeutic comprising a specific small molecule toll-like receptor (TLR) 8 agonist conjugated to a HER2-directed monoclonal antibody. TLR8 is highly expressed in myeloid cells that are prevalent in human tumors, including dendritic cells (DCs) and macrophages, and modulates their pro-inflammatory activity. SBT6050 is designed to activate human myeloid cells only in the presence of moderate-to-high HER2 expression (immunohistochemistry [IHC] 2+ or 3+) and binds to the same epitope as pertuzumab. In preclinical studies, SBT6050 potently induces a broad spectrum of antitumor immune mechanisms, including proinflammatory cytokine and chemokine production, inflammasome activation, and indirect activation of T and natural killer (NK) cells. TLR8 agonism has emerged as a promising approach to overcome resistance to immune checkpoint inhibitors in tumors lacking T-cell infiltrates, as these cancers are often replete with myeloid cells. Using an SBT6050 mouse surrogate in vivo, curative single-agent efficacy was observed in multiple murine tumor models, including a model deficient in T, B, and NK cells. In preclinical toxicology studies in nonhuman primates, SBT6050 was well tolerated, supporting a first-in-human starting dose that is predicted to be pharmacologically active, with a short escalation to projected clinically active doses. Preclinical studies also support combinations with checkpoint inhibitors and with trastuzumab to further enhance antitumor activity.MethodsSBT6050-101 is an ongoing phase 1/1b, first-in-human, open-label, multicenter study. Eligible subjects are adults with histologically confirmed, HER2-expressing (IHC 2+ or 3+), locally advanced (unresectable) and/or metastatic cancer. Subjects must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and have previously received all therapies known to confer clinical benefit. SBT6050 is given subcutaneously every 2 weeks and treatment may continue for up to 2 years or until disease progression, unacceptable toxicity, or other reason for discontinuation. The trial objectives are to evaluate the safety and tolerability of SBT6050 and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). The study has 2 parts: Part 1, consisting of a dose escalation using a standard 3+3 design, and Part 2, consisting of 5 parallel expansion cohorts based on tumor type and HER2 expression level and treated with SBT6050 at the RP2D. Pharmacokinetics, immunogenicity, and antitumor activity will be evaluated and pharmacodynamic markers of myeloid cell activation will be assessed in peripheral blood and on-treatment tumor biopsies.ResultsN/AConclusionsN/ATrial RegistrationNCT04460456Ethics ApprovalThe study was approved by MD Anderson Cancer Center Institutional Review Board, approval number 2020-0326 MOD001.

Epacadostat plus pembrolizumab in patients with advanced RCC: Preliminary phase I/II results from ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4515-4515 ◽  
Author(s):  
Primo Lara ◽  
Todd Michael Bauer ◽  
Omid Hamid ◽  
David C. Smith ◽  
Thomas Gajewski ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Antiangiogenic Therapy ◽  
Safety Data ◽  
Open Label ◽  
Multiple Tumor ◽  
Open Label Phase ◽  
Immunotherapeutic Strategy ◽  
Grade 3 ◽  
Tumor Types

4515 Background: Epacadostat (E) is a potent oral inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression. Preclinical and clinical data suggest that epacadostat has antitumor activity when combined with checkpoint inhibitors, including the PD-1 inhibitor pembrolizumab (P). ECHO-202/KEYNOTE-037 is an ongoing open-label, phase 1/2 (P1/2) study evaluating E + P in multiple tumor types. We report preliminary P1/2 efficacy and safety data for the advanced renal cell carcinoma (RCC) cohort as of a 29OCT2016 data cutoff. Methods: Eligible patients (pts) had advanced clear-cell RCC, prior antiangiogenic therapy (tx), and no prior checkpoint inhibitor tx. In P1 dose escalation (3+3+3), pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for P2 cohort expansion. Response was assessed in RECIST 1.1 evaluable pts. Safety/tolerability was assessed in pts receiving ≥1 E + P dose. Results: 33 pts (P1, n = 11; P2, n = 22) were enrolled (median age, 63 years; 70% men; 97% white; MSKCC criteria of favorable, intermediate, and poor in 6%, 64%, and 12% of pts, respectively). Of 30 efficacy-evaluable pts, 63% (n = 19) had 0–1 prior tx and 37% (n = 11) had ≥2 prior tx for advanced disease. ORR (CR+PR) and DCR (CR+PR+SD) for pts with 0–1 prior tx was 47% (9/19; 1 CR, 8 PR) and 58% (11/19; 1 CR, 8 PR, 2 SD), respectively; for pts with ≥2 prior tx, ORR and DCR were 0% and 36% (4/11; all SD). At data cutoff, 9/9 responses were ongoing (range, 1+ to 372+ days). PFS and biomarker analyses are ongoing. TRAEs occurring in ≥10% of the 33 pts included fatigue and rash (36% each); and arthralgia, diarrhea, pruritus, and pyrexia (12% each). Grade ≥3 TRAEs occurred in 15% of pts (none in > 1 pt). Two pts discontinued due to TRAEs (grade 3 autoimmune hepatitis, n = 1; grade 3 aseptic meningitis/headache/nausea/vomiting/anxiety, n = 1). Conclusions: E + P was generally well tolerated and associated with encouraging response outcomes in advanced RCC pts with 0–1 prior line of tx. E + P represents a novel immunotherapeutic strategy. A phase 3 RCC study is planned. Clinical trial information: NCT02178722.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

scholarly journals Nonclinical Development of SRK-181: An Anti-Latent TGFβ1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors

2021 ◽  
pp. 109158182199894
Author(s):  
Brian T. Welsh ◽  
Ryan Faucette ◽  
Sanela Bilic ◽  
Constance J. Martin ◽  
Thomas Schürpf ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Checkpoint Inhibitors ◽  
Human Peripheral Blood ◽  
Phase 1 ◽  
Locally Advanced ◽  
Acquired Resistance ◽  
Transforming Growth Factor Β ◽  
Human Antibody ◽  
Primary Resistance

Checkpoint inhibitors offer a promising immunotherapy strategy for cancer treatment; however, due to primary or acquired resistance, many patients do not achieve lasting clinical responses. Recently, the transforming growth factor-β (TGFβ) signaling pathway has been identified as a potential target to overcome primary resistance, although the nonselective inhibition of multiple TGFβ isoforms has led to dose-limiting cardiotoxicities. SRK-181 is a high-affinity, fully human antibody that selectively binds to latent TGFβ1 and inhibits its activation. To support SRK-181 clinical development, we present here a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies showed that SRK-181 has no effect on human platelet function and does not induce cytokine release in human peripheral blood. Four-week toxicology studies with SRK-181 showed that weekly intravenous administration achieved sustained serum exposure and was well tolerated in rats and monkeys, with no treatment-related adverse findings. The no-observed-adverse-effect levels levels were 200 mg/kg in rats and 300 mg/kg in monkeys, the highest doses tested, and provide a nonclinical safety factor of up to 813-fold (based on Cmax) above the phase 1 starting dose of 80 mg every 3 weeks. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that SRK-181 is a selective inhibitor of latent TGFβ1 that does not produce the nonclinical toxicities associated with nonselective TGFβ inhibition. These data support the initiation and safe conduct of a phase 1 trial with SRK-181 in patients with advanced cancer.

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

scholarly journals Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 726
Author(s):  
Christopher Groth ◽  
Ludovica Arpinati ◽  
Merav E. Shaul ◽  
Nina Winkler ◽  
Klara Diester ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Receptor Expression ◽  
Myeloid Derived Suppressor Cells ◽  
Melanoma Progression ◽  
Relative Contribution ◽  
Immunosuppressive Tumor Microenvironment ◽  
Metastatic Sites

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.

scholarly journals Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 678 ◽  
Author(s):  
Adrien Procureur ◽  
Audrey Simonaggio ◽  
Jean-Emmanuel Bibault ◽  
Stéphane Oudard ◽  
Yann-Alexandre Vano
Keyword(s):  
Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Mitotic Cell ◽  
Immunogenic Cell Death ◽  
Dna Damages ◽  
Multiple Tumor ◽  
Tumor Types

The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

scholarly journals Association of the Lung Immune Prognostic Index with Immunotherapy Outcomes in Mismatch Repair Deficient Tumors

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3776
Author(s):  
Edouard Auclin ◽  
Perrine Vuagnat ◽  
Cristina Smolenschi ◽  
Julien Taieb ◽  
Jorge Adeva ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Prognostic Index ◽  
Predictive Marker ◽  
Risk Groups ◽  
Two Factors ◽  
One Year ◽  
Metastatic Sites ◽  
Tumor Types

Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR > 3 and LDH > upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS < 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p <0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46–8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMR patients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials.

scholarly journals Improved Bioavailability with Dry Powder Cannabidiol Inhalation: A Phase 1 Clinical Study

2021 ◽  
Author(s):  
Orrin Devinsky ◽  
Kelly Kraft ◽  
Lorraine Rusch ◽  
Melanie Fein ◽  
Andrea Leone-Bay
Keyword(s):  
Clinical Study ◽  
Phase 1 ◽  
Dry Powder

scholarly journals 411 Novel intratumoral agent, INT230–6 induces cancer cell death, increases tumor infiltrates and results in durable benefit alone or in combination with pembrolizumab in refractory patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A436-A436
Author(s):  
Anthony El-Khoueiry ◽  
Jacob Thomas ◽  
Anthony Olszanski ◽  
Nilofer Azad ◽  
Lewis Bender ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Systemic Exposure ◽  
Systemic Circulation ◽  
Cancer Center ◽  
Advanced Malignancy

BackgroundINT230-6 is a novel formulation of cisplatin and vinblastine with an amphiphilic cell penetration enhancer that has been shown to enhance dispersion of the drug throughout tumors and allow diffusion into cells when given intratumorally. In preclinical models, INT230-6 has resulted in cell death, dendritic cell influx, antigen presentation and T-cell engagement with strong synergy when combined with checkpoint inhibitorsMethodsThis phase 1/2 study evaluated Q2week injections of INT230-6 x 5 dosed by tumor volume alone or with 200 mg pembrolizumab IV Q3 weeks. Eligble patients had any advanced malignancy refractory to standard therapy with an injectable tumor.ResultsSixty subjects (median 3 prior therapies (range 0–10)) were enrolled (53 monotherapy, 7 combo). Median age was 60 (42–85). 19 different cancer types were accrued with breast cancer and sarcoma being the most frequent. Over 200 deep tumor injections were administered at doses of up to 172 ml of INT230-6 (86 mg of CIS, 17 mg of Vin). PK analysis revealed <5% of the drugs were measured in systemic circulation, indicative of minimal systemic exposure. There was no dose limiting toxicity. The most frequent monotherapy drug related AE’s reported were: injection-site pain 58%, nausea 37%, fatigue 33%, and vomiting 27% with only 18% of subjects experiencing a grade 3 AE (no grade 4 or 5). Rates were comparable for the single agent INT230-6 and the combination with pembrolizumab. In the overall monotherapy cohort, patients completing all 5 doses of INT230-6 over 56 days (n=16), the median overall survival has not yet been reached. after a median followup of 408 days. In the 5 evaluable patients who received the pembrolizumab combination, the median TTP has not been reached with a median follow up of 6 mo. Paired biopsies (pre, 1 month) were available in 10 monotherapy patients and revealed a median of 63% reduction in viable cancer cells on H&E (30% had no viable cancer) that was also associated with qualitative decreases in Ki67, increases of CD4 and CD8 T-cells and reduction in FoxP3 Tregs. Despite receiving only 2 month of monotherapy, short half lives of the active agents, and no subsequent therapies, 8 injected tumors continued to regress past 1 year.ConclusionsINT230-6 is well tolerated when administered intratumorally alone or in combination with pembrolizumab. Pharmacodynamic assessments provides proof of concept that this drug can reduce viable cancer cells and increases CD4/CD8 T-cell infiltrates leading to durable clinical benefit off treatment.Trial RegistrationNCT 03058289Ethics ApprovalThe study was approved by USC, Princess Margaret Cancer Center, Fox Chase, UMass, Columbia, and Johns Hopkins Institution’s Ethics BoardConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal

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