Executive Summary / Key Takeaways

• Calidi Biotherapeutics is a clinical-stage immuno-oncology company developing proprietary allogeneic stem cell-based and enveloped platforms designed to enhance the delivery and potency of oncolytic viruses for cancer treatment, aiming for potentially universal therapies.
• The company's pipeline includes CLD-101 (NeuroNova) in Phase 1/1b2 trials for High Grade Glioma, CLD-201 (SuperNova) with IND approval for solid tumors, and preclinical programs CLD-301 (AAA stem cells) and CLD-400 (RTNova enveloped viruses).
• Financially, Calidi reported a net loss of $5.062 million for Q1 2025, a decrease from $7.225 million in Q1 2024, driven by reduced R&D and G&A expenses; however, cash burn remains significant, with $7.1 million used in operations in Q1 2025.
• As of March 31, 2025, the company held $10.6 million in cash, but management has concluded there is substantial doubt about its ability to continue as a going concern within 12 months, necessitating significant additional funding.
• The investment thesis hinges on the successful clinical validation of its differentiated technology platforms and the ability to secure sufficient capital to advance its pipeline against a backdrop of intense competition and inherent biotech development risks.

Unpacking the Calidi Biotherapeutics Story

Calidi Biotherapeutics, Inc. (NYSEAMERICAN:CLDI) is charting a course in the complex landscape of immuno-oncology, focusing on a novel approach: leveraging allogeneic stem cells and enveloped platforms to deliver and potentiate oncolytic viruses. The company's ambition is significant – to develop off-the-shelf therapies capable of targeting and eliminating a broad spectrum of cancers, potentially creating "universal treatments" that transcend tumor genetic profiles. This strategic focus positions Calidi within a highly competitive and rapidly evolving sector, where innovation in delivery and mechanism of action is paramount.

The current iteration of Calidi was formed through a Business Combination in September 2023, bringing together the assets and strategic vision of the pre-merger entity with a public listing structure. Prior to this, the company had been diligently building its foundational elements: licensing key technologies, establishing intellectual property, conducting preclinical studies, and laying the groundwork for clinical trials. This history underscores a deliberate, science-first approach to tackling cancer, rooted in the potential of oncolytic virotherapy enhanced by cellular delivery.

The Technological Edge: Stem Cells as Trojan Horses

At the heart of Calidi's strategy lies its differentiated technology platforms, primarily NeuroNova, SuperNova, and the emerging RTNova. These platforms utilize allogeneic stem cells or cell membrane envelopes as sophisticated delivery vehicles for oncolytic viruses. The core premise is that these cellular carriers can address key limitations of traditional oncolytic virus delivery.

Specifically, the technology is designed to:

• Protect Oncolytic Viruses: Shield the viruses from rapid inactivation by the patient's innate immune system, including complement inactivation. This protection is critical for allowing the viruses to reach tumor sites in sufficient numbers.
• Support Viral Amplification: Provide a supportive environment within the allogeneic cells for the oncolytic viruses to replicate effectively.
• Modify the Tumor Microenvironment: Influence the local tumor environment to enhance tumor cell targeting and facilitate prolonged viral activity at the disease site.

While specific, quantifiable performance metrics like "X% increase in viral delivery" or "Y% reduction in immune clearance" directly tied to the technology's mechanism in a comparative sense are not readily available, the strategic intent and potential benefits are clear. The company's preclinical studies for programs like RTNova have shown early signs of resistance to human humoral immunity and the capability to target distant tumors, suggesting the delivery method is conferring a tangible advantage in systemic administration. The goal of these platforms is to improve upon the efficacy and safety profiles of existing or competitor oncolytic virus approaches by ensuring more viruses reach the tumor and persist longer, potentially leading to improved anti-tumor immunity and reduced recurrence.

Calidi's R&D efforts extend beyond the lead candidates. The CLD-301 program explores Adult Allogeneic Adipose-derived (AAA) stem cells for broader regenerative medicine applications, a strategic move to potentially diversify the technology's use cases. The CLD-400 (RTNova) program, building on prior research, specifically targets lung cancer and metastatic solid tumors, focusing on developing an enveloped vaccinia virus capable of surviving in the bloodstream for systemic delivery – a critical challenge in virotherapy. The stated goal for RTNova is to achieve systemic antitumor effects and potential synergy with other immunotherapies. The "so what" for investors is that these technological differentiators, if validated through clinical trials, could represent a significant competitive moat, enabling Calidi to potentially achieve better clinical outcomes, command premium pricing, or access broader patient populations compared to therapies limited by delivery challenges.

Pipeline Progress and Operational Realities

Calidi's pipeline reflects its multi-platform approach. The most advanced program, CLD-101 (NeuroNova), is in clinical development for High Grade Glioma (HGG). A completed Phase 1 trial in newly diagnosed HGG demonstrated the single administration of CLD-101 was well tolerated. Building on this, Northwestern University began recruiting for a Phase 1b/2 trial in Q1 2025 to evaluate repeated dosing in newly diagnosed HGG, including extensive biomarker analysis. However, the continuation of this trial is contingent on the resumption of frozen National Cancer Institute (NCI) sponsored grants, highlighting a specific operational dependency. Separately, a Phase 1 study of repeated intracerebral doses of CLD-101 in recurrent HGG (NNV2), run by City of Hope, began in May 2023 and was enrolling its fourth cohort as of January 2024.

The SuperNova platform's lead candidate, CLD-201 (SNV1) for solid tumors, achieved a significant milestone with its IND application approved by the FDA in March or April 2025 (filings indicate slightly conflicting dates). The company plans to seek non-dilutive funding to support the commencement of a Phase 1 clinical trial for CLD-201 by the end of 2025.

These clinical and preclinical activities are the primary drivers of the company's operating expenses. For the three months ended March 31, 2025, research and development expenses totaled $2.425 million, a decrease from $2.743 million in the same period of 2024. This $0.3 million decrease was attributed primarily to lower salaries, benefits, and drug manufacturing/preclinical costs, partially offset by increased consulting. General and administrative expenses also saw a significant reduction, falling from $4.009 million in Q1 2024 to $2.637 million in Q1 2025, a $1.372 million decrease driven mainly by lower salaries, stock-based compensation, legal, and insurance costs.

Competitive Landscape: Innovation vs. Scale

Calidi operates within a highly competitive environment populated by both large pharmaceutical companies and numerous smaller biotechnology firms. Key direct competitors identified include SIGA Technologies (SIGA), which has antiviral expertise and emerging oncology collaborations; CG Oncology (CGON), focused on oncolytic viruses for bladder cancer; CRISPR Therapeutics (CRSP), a leader in gene editing; and large players like Gilead Sciences (GILD) with significant oncology portfolios, often built through acquisitions.

Calidi's competitive positioning is defined by its unique delivery platforms. While companies like CGON and others develop oncolytic viruses, Calidi's use of allogeneic stem cells and enveloped viruses aims to overcome systemic delivery challenges that can limit the effectiveness of other virotherapies. The company's preclinical data suggesting resistance to human humoral immunity for RTNova is a potential advantage in achieving systemic reach, a critical factor for treating metastatic disease. The potential for lower manufacturing costs per dose via stem cell amplification, as suggested by competitive analysis, could also provide a strategic edge against more complex or costly manufacturing processes used by some competitors, such as certain gene therapies or CAR-T approaches.

However, Calidi faces significant disadvantages compared to larger, more established players and even better-funded peers. Companies like Gilead possess vast financial resources, established commercial infrastructure, and diversified pipelines that provide stability. CRISPR Therapeutics benefits from being a leader in the high-profile gene-editing space with strong partnerships and significant capital. CG Oncology, following its IPO, has a bolstered balance sheet to advance its specific bladder cancer focus. Calidi's relatively smaller scale and, critically, its constrained liquidity position its technology and pipeline at risk if funding cannot be secured. While Calidi's technology may offer potential advantages in efficacy or cost for specific applications, translating these into market share requires successful clinical trials and commercialization capabilities that well-funded competitors are better positioned to execute. Indirect competitors, such as contract manufacturing organizations offering more efficient production methods (like Cellares), could also pressure margins across the sector, including potentially impacting Calidi's future manufacturing costs or strategic options.

Financial Health and the Going Concern Question

Calidi's financial state reflects its stage of development: significant investment in R&D with no product revenue. The net loss for the three months ended March 31, 2025, was $5.062 million, leading to an accumulated deficit of $126.7 million as of that date. Cash used in operating activities was $7.131 million in Q1 2025, an increase from $3.831 million in Q1 2024, indicating an acceleration in cash burn despite the decrease in operating expenses, likely due to changes in working capital.

As of March 31, 2025, the company had $10.61 million in cash. While recent financing activities provided significant inflows – $3.8 million gross from the January CMPO, $3.9 million gross from the March Registered Direct Offering, and $2.9 million gross from the At the Market (ATM) offering in Q1 2025 – these proceeds were partially offset by debt repayments and operating expenses.

The critical financial reality is that management has explicitly stated there is "substantial doubt about the Company’s ability to continue as a going concern within 12 months from the date of issuance of the unaudited condensed consolidated financial statements" (filed May 14, 2025). This assessment is based on the current liquidity resources and expected continued operating losses and negative cash flows. The company's ability to continue is dependent on raising additional funding through equity or debt financings, collaborations, or other sources. The risk is that such financing may not be available when needed, on favorable terms, or at all. Further equity issuances, while necessary for survival, will inevitably lead to dilution for existing shareholders, particularly those who purchased shares at higher prices. The company has actively utilized its ATM facility and conducted public/registered offerings, demonstrating a reliance on capital markets that can be volatile.

Outlook and Key Considerations

Calidi's outlook is directly tied to its ability to execute on its clinical development plans and secure necessary funding. The stated goal of initiating a Phase 1 trial for CLD-201 (SNV1) by the end of 2025 is a key near-term objective, contingent on obtaining non-dilutive funding. The progress of the CLD-101 trials, particularly the Phase 1b/2 study at Northwestern, is also critical, though currently impacted by the NCI funding freeze.

Strategic initiatives like the formation of Nova Cell and Redtail Biopharma signal a long-term vision to expand the application of their stem cell technology beyond oncology and explore systemic virotherapies more broadly. The recent leadership transition, with Eric Poma appointed CEO and James Schoeneck as Chairman following Allan Camaisa's resignation, marks a new chapter for the company. While the filing states this change was not due to disagreements, leadership transitions can impact strategic direction and execution.

Key factors for investors to watch include:

• Success in securing additional funding, particularly non-dilutive sources for CLD-201.
• Resolution of the NCI funding freeze and progress in the CLD-101 Phase 1b/2 trial.
• Initiation and initial data from the CLD-201 Phase 1 trial.
• Updates on preclinical programs like RTNova and AAA stem cells.
• Outcomes of ongoing legal proceedings, which could impact financial resources or management focus.
• The company's ability to manage cash burn effectively.

Conclusion

Calidi Biotherapeutics possesses a compelling scientific foundation with its differentiated stem cell and enveloped virus delivery platforms, offering a unique approach in the competitive immuno-oncology space. The potential for these technologies to improve the efficacy and reach of oncolytic virotherapies represents the core of the investment thesis. However, this potential is currently overshadowed by significant financial challenges, including recurring losses, substantial cash burn, and the explicit going concern warning. The company's ability to translate its technological promise into clinical and commercial success is entirely dependent on its capacity to raise substantial additional capital in a challenging market environment. While recent financing efforts have provided a temporary buffer, the need for further funding is immediate and critical. Investors considering Calidi must weigh the long-term potential of its innovative pipeline against the near-term risks associated with its financial viability and the inherent uncertainties of clinical development in a highly competitive field. The story of Calidi is one of scientific aspiration meeting financial exigency, where the outcome will be determined by both clinical execution and capital formation.