Combined paclitaxel/CKM regimen was safe, with desirable TME changes and preliminary indications of promising pCR+ypTmic of 66%, comparable to the combination of NAC with pembrolizumab.

P2, N=90, Recruiting, AIM ImmunoTech Inc. | Trial completion date: Apr 2028 --> Jul 2028 | Trial primary completion date: Mar 2028 --> Jun 2028

P2, N=24, Recruiting, Roswell Park Cancer Institute | Trial completion date: Aug 2025 --> Nov 2025 | Trial primary completion date: Aug 2025 --> Nov 2025

P2, N=90, Recruiting, AIM ImmunoTech Inc. | Trial completion date: Jul 2027 --> Apr 2028 | Trial primary completion date: Jun 2027 --> Mar 2028

We also evaluated whether combination vaccines incorporating anti-PD-L1 checkpoint blockade and/or a chemokine-modulating (CKM; IFNα + TLR3-L [rintatolimod] + Celecoxib) regimen would improve T cell infiltration/functionality in tumors yielding enhanced treatment benefits. Peptide-based vaccines that selectively target either melanoma antigens or TBVAs elicited a CD8+ T cell repertoire recognizing both tumor cells and tumor-associated VECs and pericytes in vitro, consistent with a treatment-induced epitope spreading mechanism. Notably, combination vaccines including anti-PD-L1 + CKM yielded superior therapeutic effects on tumor growth and animal survival, in association with the potentiation of polyfunctional CD8+ T cell reactivity against both tumor cells and tumor-associated vascular cells and a pro-inflammatory TME.

P2, N=30, Suspended, Roswell Park Cancer Institute | Trial completion date: May 2024 --> May 2026 | Trial primary completion date: May 2024 --> May 2026

P1/2, N=45, Recruiting, Robert Edwards | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

P2, N=24, Recruiting, Roswell Park Cancer Institute | Trial completion date: Dec 2025 --> Aug 2025

P1/2, N=12, Recruiting, Roswell Park Cancer Institute | Trial completion date: Dec 2025 --> Jun 2025 | Trial primary completion date: Dec 2025 --> Jun 2025

This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunological tolerance by enhancing anti-tumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes.

P2, N=30, Suspended, Roswell Park Cancer Institute | Trial completion date: Nov 2024 --> May 2024 | Trial primary completion date: Nov 2023 --> May 2024

P1/2, N=12, Recruiting, Roswell Park Cancer Institute | Not yet recruiting --> Recruiting

P2, N=24, Recruiting, Roswell Park Cancer Institute | Suspended --> Recruiting

P2, N=80, Completed, AIM ImmunoTech Inc. | Active, not recruiting --> Completed

Short-term systemic CKM selectively increases CTL numbers and CTL/Treg ratios in the TME, while transiently decreasing CTL numbers in the blood. Transient effects of CKM suggest that its simultaneous application with checkpoint blockade and other forms of immunotherapy may be needed for optimal outcomes.

Combination of NAC with pembrolizumab, the new standard of care in TNBC, increases the pCR rate to 65% but is associated with significant and often permanent immune-related toxicities...We hypothesized that the combination of CKM with paclitaxel-based NAC will promote selective CTL infiltration into TNBC, and along with doxorubicin/cyclophosphamide (AC), will result in higher rate of pCR, translating into improved RFS and OS... We have observed preliminary indications of safety and good tolerability of the combination of CKM regimen with paclitaxel, with promising pCR + ypTmic of 66%. RNA sequencing indicates that CKM may drive CD8+ T cells from the blood into the tumor.

P1/2, N=12, Not yet recruiting, Roswell Park Cancer Institute | Trial completion date: Jun 2025 --> Dec 2025 | Initiation date: Sep 2023 --> Dec 2023 | Trial primary completion date: Jun 2025 --> Dec 2025

P1/2, N=43, Not yet recruiting, Joachim Aerts, MD PhD | Initiation date: Jul 2023 --> Dec 2023

P1/2, N=12, Not yet recruiting, Roswell Park Cancer Institute | Trial completion date: Jul 2027 --> Jun 2025 | Trial primary completion date: Jul 2026 --> Jun 2025

Lastly, we identified fifteen genes, altered with a Log FOC > |1.0| in rintatolimod-treated CFPAC-1 cells, which were significantly related to three transcription factors (NFKB1, RELA, and SP1) regulating the TLR-3 signaling pathway. In conclusion, we propose that rintatolimod treatment might have a direct TLR-3-dependent anti-tumoral effect on pancreatic cancer cells expressing TLR-3.

P1/2, N=43, Not yet recruiting, Joachim Aerts, MD PhD

Treatment of patients with locally advanced pancreatic cancer after FOLFIRINOX with rintatolimod may induce markers of dendritic cells and T cells in a subgroup of patients. The absence of these markers could predict tumor progression after FOLFIRINOX. Further identification of T lymphocyte and dendritic cell subsets using flow-cytometry analysis will be presented.

P2, N=90, Recruiting, AIM ImmunoTech Inc. | Initiation date: Mar 2023 --> Jun 2023

P1, N=9, Completed, Roswell Park Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Feb 2024 --> Feb 2023

P1/2, N=12, Not yet recruiting, Roswell Park Cancer Institute | Trial completion date: Apr 2027 --> Jul 2027 | Trial primary completion date: Apr 2026 --> Jul 2026

P1, N=9, Active, not recruiting, Roswell Park Cancer Institute | Suspended --> Active, not recruiting | N=24 --> 9 | Trial completion date: May 2023 --> Feb 2024

P1/2, N=64, Suspended, Roswell Park Cancer Institute | Recruiting --> Suspended

P1/2, N=25, Suspended, Roswell Park Cancer Institute | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

We hypothesized that the combination of CKM with paclitaxel will promote selective CTL infiltration into TNBC, and along with doxorubicin/cyclophosphamide (AC), will result in higher rate of pCR, translating into improved RFS and OS. The treatment was well-tolerated and no DLTs were observed and we determined RP2D for future studies. We observed promising clinical activity with pCR + ypTmic rate of 66%, comparable to pembrolizumab combination with NAC. A larger phase II study is being designed to confirm the observed efficacy and to determine if CKM regimen would be a safer short-term alternative to pembrolizumab or if CKM can overcome the resistance to the standard pembrolizumab/NAC therapy.

CKM/Paclitaxel was followed by standard dose-dense doxorubicin and cyclophosphamide (AC) and surgery. Conclusions The treatment was well tolerated, with promising clinical activity of pCR + ypTmic at 66%, comparable to pembrolizumab/NAC. Upcoming phase II study in early stage TNBC is planned to determine if CKM can be used as an alternative to pembrolizumab or to overcome pembrolizumab/NAC resistance.

P1, N=24, Suspended, Roswell Park Cancer Institute | Trial primary completion date: Aug 2022 --> May 2022

P1, N=24, Suspended, Roswell Park Cancer Institute | Recruiting --> Suspended

We hypothesize that a combination of intraperitoneal (IP) chemotherapy (cisplatin) with dual agent immunotherapy using intravenous (IV) pembrolizumab (anti-PD1) and IP rintatolimod (TLR-3 agonist) will help overcome immune suppressive mechanisms for improved tumor response by promoting increased T cell chemotaxis and cytolytic function. To test our hypothesis, we are running an investigator initiated, phase II, single arm, efficacy/safety trial (NCT03734692). In this ongoing Phase II study, a total of 17 patients were enrolled and 13 were evaluable for response. The observed clinical responses were: 2 complete responses (15.4%), 3 partial responses (23.1%), 3 stable disease (23.1%), 5 progressions (38.4%) for an clinical benefit rate (CR+PR+SD) of 61.6%. From 13 patients, 7 IP wash samples were collected at serial time points.

Our results identify an undesirable aspect of paclitaxel’s impact on breast cancer. The ability of CKM to enhance the expression of CTL/NK cell attractants and suppress the production of Treg/MDSC attractants produced by paclitaxel provides a strong rationale for combined use of CKM in taxane-based chemo-immunotherapy of breast cancer and potentially other diseases.

The chemokine-modulating IP-CITC is safe, tolerable, and associated with ISG changes that favor CTL chemoattraction and function. This combination (plus DC vaccine) will be tested in a phase II trial.

P1/2, N=25, Suspended, Roswell Park Cancer Institute | Trial completion date: Sep 2023 --> Jun 2025 | Trial primary completion date: May 2023 --> Dec 2024

P1/2, N=64, Recruiting, Roswell Park Cancer Institute | Trial completion date: Nov 2022 --> Nov 2023 | Trial primary completion date: Nov 2021 --> Nov 2023

P1/2, N=3, Terminated, Abramson Cancer Center of the University of Pennsylvania | Completed --> Terminated; Did not meet criteria laid out in Phase 1 to continue to Phase 2

P2a, N=15, Completed, Roswell Park Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Nov 2021 --> Aug 2021

P1/2, N=64, Recruiting, Roswell Park Cancer Institute | Trial completion date: Apr 2022 --> Nov 2022

Furthermore, Rintatolimod treatment increased the expression of angiogenesis-related genes without promoting fibrosis, which is the main cause of death in patients with COVID-19. We conclude that Rintatolimod could be considered an early additional treatment option for cancer patients who are infected with SARS-CoV-2 to prevent the complicated severity of the disease.

P1/2, N=64, Recruiting, Roswell Park Cancer Institute | N=44 --> 64 | Trial completion date: Sep 2021 --> Apr 2022