Calidi Biotherapeutics Announces IL15 Superagonist as First Payload to be Delivered by Systemic Antitumor Virotherapy  Platform at AACR Annual Meeting

Rhea-AI Summary

Calidi Biotherapeutics (NYSE: CLDI) has announced IL15 superagonist as the first payload for its systemic antitumor virotherapy platform, RTNova. The announcement was made at the AACR Annual Meeting on April 27, 2025.

The RTNova platform utilizes an engineered vaccinia virus designed for tumor-selective targeting and produced in an enveloped form that enables survival in bloodstream circulation to reach metastatic tumor sites. Preclinical data demonstrates that the platform's ability to express IL15 superagonist specifically in tumor microenvironments significantly increases complete tumor elimination responses after a single systemic administration.

This advancement represents a significant step in treating metastatic cancers, as it overcomes the limitations of traditional intratumoral oncolytic viruses by enabling systemic administration. The platform can also be adapted to deliver various therapeutic payloads, allowing customized treatment approaches for different tumor types.

Positive

• Successful preclinical data showing increased tumor elimination responses
• Platform enables systemic delivery to target metastatic tumors, expanding market potential
• Versatile platform capable of delivering multiple therapeutic payloads
• Technology addresses limitation of current intratumoral treatments

Negative

• Still in preclinical stage, requiring extensive clinical trials
• No human efficacy data available yet

Insights

Oncology Research Expert

Calidi's new tumor-targeted delivery system for IL15 superagonist shows promising preclinical results, addressing key limitations in cancer therapy delivery.

The selection of IL15 superagonist as the first payload for Calidi's RTNova platform represents a scientifically calculated approach to a significant challenge in immunotherapy. IL15 superagonist is known to stimulate powerful anti-tumor immune responses, but its clinical application has been hampered by severe systemic toxicity - a problem their targeted delivery method aims to solve.

The data presented at AACR demonstrates that Calidi's approach increased complete responses (tumor eliminations) in preclinical models after just a single administration. This suggests the potential for enhanced efficacy while potentially reducing off-target effects through tumor-specific expression.

The RTNova platform's key innovation is the enveloped vaccinia virus designed to survive bloodstream circulation - addressing one of the primary limitations of oncolytic virotherapy. Current approved oncolytic viruses require direct intratumoral injection, restricting their use to accessible tumors. A systemically deliverable alternative would significantly expand treatment possibilities for metastatic disease.

While these preclinical results are encouraging, several challenges remain before clinical validation, including potential immune neutralization of the virus, manufacturing consistency, and dose optimization. The tumor-selective replication mechanism will need to demonstrate robust safety and specificity in clinical settings.

The platform's versatility for delivering different payloads offers flexibility to tailor approaches for various tumor types, potentially expanding its applicability across multiple cancer indications if the core delivery technology proves successful.

Biotechnology Investment Analyst

Calidi's preclinical progress with systemically-delivered IL15 superagonist represents promising technology advancement, but remains years from potential commercialization.

This announcement represents an important technological milestone in Calidi's development of their RTNova platform. The company is addressing two significant limitations in current cancer therapies: the toxicity of systemic IL15 administration and the inability of conventional oncolytic viruses to reach metastatic tumors.

The selection of IL15 superagonist as their lead payload is strategically sound. This cytokine has demonstrated potent anti-tumor activity but has been clinically by toxicity concerns - precisely the problem Calidi's tumor-targeted approach aims to solve.

The platform's systemic administration capability is particularly noteworthy as it potentially expands the addressable market beyond injectable tumors to include metastatic disease - a substantial market with high unmet medical need. If successful, this would differentiate Calidi from competitors focused on intratumoral administration.

However, investors should recognize that this announcement represents preclinical progress only. The data showing increased complete responses in animal models is encouraging but faces significant translational hurdles before human application. The typical development timeline would place potential clinical trials at least 1-2 years away, with potential approval much further in the future.

The platform approach creates multiple potential development pathways, as success with IL15 delivery could validate the system for other therapeutic payloads. This flexibility provides technological optionality but also requires significant development resources.

This announcement confirms Calidi's continued progress with their differentiated technology platform but represents an incremental scientific advancement rather than a near-term commercial catalyst.

SAN DIEGO, April 28, 2025 (GLOBE NEWSWIRE) -- Calidi Biotherapeutics Inc. (NYSE American: CLDI) (“Calidi”), a clinical-stage biotechnology company developing a new generation of targeted antitumor virotherapies, today announced the selection of IL15 superagonist (Il15-IL15Ra) as the first payload to be delivered into tumors using its systemic antitumor virotherapy platform, RTNova. New preclinical data were presented at the American Association for Cancer Research (AACR) Annual Meeting on April 27, 2025, in Chicago, IL.

The first candidate developed using RTNova is a vaccinia virus (virotherapy) that is engineered to be tumor selective and produced in an enveloped form that allows the virus to survive bloodstream circulation and reach metastatic tumor sites where viral replication can destroy cancer cells while also activating an immune response. RTNova can be further engineered to deliver transgenes or gene medicines for expression in tumor cells. Data presented at AACR demonstrates that the ability of the enveloped virotherapy to express IL15 superagonist specifically in the tumor microenvironment measurably increases the number of complete responses, or tumor eliminations, in preclinical models after a single systemic administration.

“IL15 superagonist is a potent cytokine capable of generating robust and durable immune responses against tumors but can induce severe toxicity when administered systemically” said Antonio F. Santidrian, PhD, Chief Scientific Officer at Calidi. “By using tumor-targeted virotherapies systemically delivered to express therapeutic proteins like IL-15 superagonist directly into the tumor microenvironment, we believe we can effectively boost immune response against the tumors precisely where it is needed while minimizing systemic toxicity”.

“While intratumoral use of oncolytic viruses has shown positive clinical results, their applicability has been limited to injectable cancers,” said Eric Poma, PhD, Chief Executive Officer at Calidi. “Our RTNova platform builds on the clinical success of current intratumoral oncolytic viruses but is designed for systemic administration, allowing us to target metastatic disease patients with high unmet need. RTNova also allows for the delivery of payloads like IL-15 superagonist to the tumor microenvironment, inducing a profound anti-tumor immune activation.”

With the RTNova platform, Calidi Biotherapeutics is pioneering the systemic delivery of virotherapies, a major step forward in treating metastatic cancers. This adaptable platform can also deliver different therapeutic payloads, allowing a bespoke approach to candidate design determined by the intrinsic properties of different tumor types.

A copy of the poster presented at AACR featuring data on delivering IL15 superagonist is available here.

About Calidi Biotherapeutics

Calidi Biotherapeutics (NYSE American: CLDI) is a clinical-stage immuno-oncology company with proprietary technology designed to arm the immune system to fight cancer. Calidi’s novel stem cell-based platforms are utilizing potent allogeneic stem cells capable of carrying payloads of oncolytic viruses for use in multiple oncology indications, including high-grade gliomas and solid tumors. Calidi’s clinical stage off-the-shelf, universal cell-based delivery platforms are designed to protect, amplify, and potentiate oncolytic viruses leading to enhanced efficacy and improved patient safety. Calidi’s preclinical off-the-shelf enveloped virotherapies, are designed to target disseminated solid tumors. This dual approach can potentially treat, or even prevent, metastatic disease. Calidi Biotherapeutics is headquartered in San Diego, California. For more information, please visit www.calidibio.com.

Forward-Looking Statements

This press release may contain forward-looking statements for purposes of the “safe harbor” provisions under the United States Private Securities Litigation Reform Act of 1995. Terms such as “anticipates,” “believe,” “continue,” “could,” “estimate,” “expect,” “intends,” “may,” “might,” “plan,” “possible,” “potential,” “predicts,” “project,” “should,” “towards,” “would” as well as similar terms, are forward-looking in nature, but the absence of these words does not mean that a statement is not forward-looking. These forward-looking statements include, but are not limited to, statements concerning upcoming key milestones (including the reporting of interim clinical results and the dosing of patients), planned clinical trials, and statements relating to the safety and efficacy of Calidi’s therapeutic candidates in development. Any forward-looking statements contained in this discussion are based on Calidi’s current expectations and beliefs concerning future developments and their potential effects and are subject to multiple risks and uncertainties that could cause actual results to differ materially and adversely from those set forth or implied in such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that Calidi is not able to raise sufficient capital to support its current and anticipated clinical trials, the risk that early results of clinical trials do not necessarily predict final results and that one or more of the clinical outcomes may materially change following more comprehensive review of the data, and as more patient data becomes available, the risk that Calidi may not receive FDA approval for some or all of its therapeutic candidates. Other risks and uncertainties are set forth in the section entitled “Risk Factors” and “Cautionary Note Regarding Forward-Looking Statements” in the Company’s Registration Statements filed with the SEC on (i) Form S-4 filed on August 2, 2023 and the corresponding prospectus filed on August 4, 2023, and (ii) on Form S-1 filed on April 15, 2024, and the Company’s periodic reports filed with the SEC on Form 10-K filed on March 31, 2025. These reports may be amended or supplemented by other reports we file with the SEC from time to time.

Corporate Communications:

Dave Gentry, CEO
RedChip Companies, Inc.
1-407-644-4256
CLDI@redchip.com

FAQ

What is the significance of IL15 superagonist selection for CLDI's RTNova platform?

IL15 superagonist generates robust immune responses against tumors when delivered directly to tumor sites via RTNova, while minimizing systemic toxicity that typically occurs with traditional systemic administration.

How does CLDI's RTNova platform differ from traditional oncolytic virus treatments?

RTNova enables systemic administration of virotherapy to target metastatic tumors, unlike traditional oncolytic viruses that are to direct injection into accessible tumors.

What were the key findings from CLDI's preclinical data presented at AACR 2025?

The data showed increased complete tumor elimination responses after a single systemic administration of the RTNova platform delivering IL15 superagonist to tumor microenvironments.

What advantages does CLDI's RTNova platform offer for metastatic cancer treatment?

RTNova allows systemic delivery of tumor-selective virotherapy and therapeutic payloads to metastatic sites, enabling targeted treatment of widespread cancer while minimizing systemic toxicity.