nelitolimod (SD-101)

P2, N=23, Active, not recruiting, David Oh | Trial completion date: Oct 2024 --> Aug 2025 | Trial primary completion date: Oct 2024 --> Aug 2025

P1, N=20, Not yet recruiting, University of California, San Diego

The combination of neoadjuvant paclitaxel and pembrolizumab ± SD101 intratumoral injection was associated with early increases in regional lymphadenopathy on MRI despite decreased breast tumor size. Increased lymphadenopathy was not associated with node positive disease at surgery.

The SQ route of CPI delivery was equivalent to Sys in combination with nelitolimod, suggesting SQ-CPI may be a rational choice in combination with PEDD of nelitolimod for liver tumor treatment.

Treatment included weekly paclitaxel (T) plus ICI-based tx x 4 cycles, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. 6 completed investigational arms included ICIs: T+pembro x 4, T+pembro x 8 (+/- AC), T+pembro+SD101 (TLR9 agonist), T+durvalumab+olaparib, T+cemiplimab (cemi), and T+cemi+REGN3767 (anti-LAG-3)... The incidence of AI in EBC is higher than has previously been reported in advanced disease, with higher rates observed in those tx with dual immune modulation. No correlation was observed with age; correlation of AI with response predictive subtype and other clinicopathologic features is ongoing and will be presented. Given the high incidence of AI in EBC, close monitoring in the peri/postoperative setting and education of pts and providers is critical, as risk persists even after completion of tx.

"Haystack Oncology...has entered a research collaboration with TriSalus Life Sciences to evaluate therapeutic response and provide molecular insights in connection with the clinical development of TriSalus' SD-101, an investigational class C toll-like receptor-9 (TLR9) agonist. SD-101 is delivered via hepatic arterial infusion or pancreatic retrograde venous infusion in their phase 1 and 1b clinical trials using their proprietary Pressure-Enabled Drug Delivery™ (PEDD™) to overcome the challenges associated with intratumoral pressure for patients diagnosed with hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and pancreatic adenocarcinoma."

P1/2, N=89, Active, not recruiting, TriSalus Life Sciences, Inc. | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2

P1, N=80, Active, not recruiting, TriSalus Life Sciences, Inc. | Recruiting --> Active, not recruiting

Materials and The PERIO-03 trial utilizes a uniquely designed occlusive catheter (TriSalus Infusion System (TIS), TriSalus Life Sciences) for the delivery of the immunotherapeutic agent, SD-101, via Pancreatic Retrograde Venous Infusion (PRVI)... Current experience with the novel transvenous immunotherapy delivery intervention in the PERIO-03 study indicates that this PRVI procedure is technically feasible and safe.

P1, N=15, Active, not recruiting, Ronald Levy | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

P1/2, N=21, Completed, Robert Lowsky | Active, not recruiting --> Completed | N=30 --> 21 | Trial completion date: Nov 2023 --> May 2023 | Trial primary completion date: Nov 2023 --> May 2023

STUDY: Fourteen patients with low-grade lymphoma received low-dose (2Gy x 2) radiotherapy to a single tumor site followed by 5 weekly intratumoral injections of 2 mg CpG-ODN (SD-101, TriSalus Life Sciences) and 3.75 mg anti-OX40 antibody into the same site...This loss was reproduced by in vitro assays where activated blood CD4 T cells exhibited a loss of cell surface OX40 when cultured with BMS-986178... Our observations suggest that treatment with an agonistic anti-OX40 antibody induced a loss of OX40 on the cell surface of effector CD4 T cells in the tumor microenvironment. Fewer molecules of OX40 receptor may have constrained the efficacy of subsequent anti-OX40 infusions and may explain why the clinical responses observed in this study were lower than observed in our past clinical trials of in situ vaccination.

P1b/2, N=89, Recruiting, TriSalus Life Sciences, Inc. | Trial primary completion date: Aug 2023 --> Dec 2023

Pressure-Enabled Drug Delivery of toll-like receptor 9 agonist by Pancreatic Retrograde Venous Infusion with systemic anti-programmed death receptor-1 demonstrated improved pancreatic ductal adenocarcinoma tumor control in a murine pancreatic ductal adenocarcinoma model. These results support study of this combination therapy in pancreatic ductal adenocarcinoma patients and expansion of ongoing Pressure-Enabled Drug Delivery clinical trials.

For patients who received 2mg SD-101 + ICI with available liquid biopsy data, 4 of 7 demonstrated decreases in circulating tumor cells and 3 of 5 showing ctDNA decreases after the first cycle.In this first-in-human experience, HAI of SD-101 via PEDDTM was well tolerated and associated with encouraging immunologic activity. Evidence of biologic activity with 2 mg of SD-101 with nivolumab is encouraging and patients are currently enrolling at higher SD-101 dose levels + ICI.

Phase 1 clinical trials are ongoing for treatment of primary liver cancer and uveal melanoma with liver metastases using pressure-enabled drug delivery of SD-101 in combination with systemic immune checkpoint inhibitors (ICIs). Combination PMD and ICI studies are needed to inform drug combinations and dosages in syngeneic murine models of primary liver cancer and CRCLM. Subcutaneous and orthotopic tumor models are expected to demonstrate the efficacy of local PMD treatment with systemic immunotherapy.

Here we report clinical and immunological results of a phase I/II trial in non-Hodgkin Lymphoma (NCT02927964) in which we combined ISV using intratumoral SD101 (a TLR9 agonist) and low-dose radiation (2 x 2 Gy), and daily oral ibrutinib, a kinase inhibitor that modulates both B and T cells. Notably, our treatment dampened immune suppressors such as TGFß signaling, inhibitory T regulatory 1 cells, and CD8 T cell PD1 expression. These reductions correlated positively with clinical outcomes, suggesting that reversal of negative regulators was as important as induction of immune effectors in producing robust immune responses and clinically meaningful tumor responses.

P2, N=23, Active, not recruiting, Lawrence Fong | Recruiting --> Active, not recruiting | N=42 --> 23 | Trial completion date: Mar 2023 --> Oct 2023 | Trial primary completion date: Mar 2023 --> Oct 2023

Further, PBMC-derived human MDSCs express TLR9, and treatment with class C TLR9 agonists (ODN2395 and SD101) reduced the expansion of MDSC population. Regional TLR9 agonist infusion along with systemic anti-PD-1 therapy improved control of LM. With effective delivery, TLR9 agonists have the potential to favorably reprogram the liver TME through reduction of MDSCs and favorable macrophage polarization, which may improve responsiveness to systemic CPI therapy.

In vitro and in vivo antitumor immunity of R848 NE were also evaluated in combination with SD-101, a CpG-containing TLR9 agonist...The combination treatment showed a 4-fold increase in systemic TNFa production and a 2.6-fold increase in Cd8a expression in tumor tissues, suggesting strong cell-mediated immune responses against the tumor. The treatment not only demonstrated a strong antitumor immunity by TLR7/8 and TLR9 activations but also induced PD-L1 upregulation in tumors, suggesting a potential therapeutic synergy with immune checkpoint inhibitors.

Pembrolizumab combined with paclitaxel followed by doxorubicin/cyclophosphamide (P+T->AC) was evaluated in HER2- patients in the neoadjuvant I-SPY 2 TRIAL and graduated in the HER2-, HR+HER2- and triple negative (TN) signatures. Though TN patients are more responsive to Pembro+SD101 and other immunotherapies than HR+HER2- patients, many more immune biomarkers associate with pCR in the latter group. Only tumor-immune signaling signatures associate with pCR in both HR+HER2- and TN subsets. Response in the HR+HER2- subset is higher in MP2 class, high-proliferation, lower-ER tumors.

This is a retrospective study of the prospective multicenter I-SPY2 adaptive neoadjuvant trial investigating all patients enrolled at UCSF in 3 study arms between Dec 2015 and April 2021: 1) Control (weekly paclitaxel 80 mg/m 2 x 12 weeks followed by AC x 4); 2) weekly paclitaxel + pembrolizumab 200 mg IV every 3 weeks, followed by AC x 4; 3) weekly paclitaxel + every 3 week pembrolizumab + intra-tumoral SD-101 weekly x 4 then every 3 weeks x 2 followed by AC x 4. The addition of immunotherapy to standard neoadjuvant chemotherapy in the I-SPY2 trial was associated with an increase in size of ipsilateral axillary LN and/or development of new LAD on serial breast MRI imaging during the course of neoadjuvant treatment. These changes were not associated with worse pathologic response at surgery and should not be assumed to be due to disease progression. Whether these changes could reflect immunotherapy benefit needs to be investigated in a larger trial with longer follow-up.

P2; Trial completion date: Dec 2026 --> Dec 2031 | Trial primary completion date: Dec 2025 --> Dec 2030

This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.

Treatment included weekly P x 12 in combination with IT SD-101 2 mg/ml (1 ml for T2 tumors, 2 ml for >T3 tumors) weekly x 4, then q3 weeks x 2, and IV Pb q3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x 4 (SD-101+Pembro 4) . The SD-101+Pembro 4 regimen was active but did not meet the pre-specified threshold for graduation in I-SPY 2 . pCR/RCB 1 analysis suggests improved response in the HR+/HER-negative signature compared to control . The clinical significance of these findings needs to be weighed against the potential risk of immune-related toxicities.

P2, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P1 --> P2

Introduction: Local treatment with intratumoral CpG (a toll-like receptor 9 agonist, SD-101) and low-dose radiation can elicit antitumor immune responses and global tumor reduction in patients with low-grade lymphoma (Frank, Cancer Discov, 2018). Early data suggest that the combination of oral ibrutinib, intratumoral CpG, and local low-dose radiation is safe and can generate systemic antitumor immune responses and systemic tumor shrinkage in low-grade lymphoma.

P1, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P2 --> P1

P1/2, N=29, Terminated, Dynavax Technologies Corporation | Completed --> Terminated; The sponsor terminated the trial early because there was sufficient data to make a decision about SD-101 in the lymphoma development program.

P1b/2, N=241, Terminated, Dynavax Technologies Corporation | Active, not recruiting --> Terminated; A strategic restructuring including the planned conclusion of clinical oncology development programs and no further sponsoring of the development of SD-101.

P2, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | N=1920 --> 4000

P2, N=1920, Recruiting, QuantumLeap Healthcare Collaborative | Trial primary completion date: Dec 2020 --> Dec 2025

Clinical trial information: NCT04050085. Research Funding: Private, individual donor, Drug-only support from Bristol-Myers Squibb and Dynavax