(8) Undeclared, Unmodeled, Uncapped:

13 Rational MDNA11 Combinations That Expand Its Valuation Horizon

Executive Summary

This longform analysis expands the valuation horizon for MDNA11 by integrating thirteen rational, scientifically grounded combination strategies—none of which are currently modeled in Medicenna’s investor materials. Together, they represent $2.7–$4.3 billion in unmodeled NPV uplift, grounded in βγ-selective IL-2 biology and reinforced by published translational research. This is not a speculative projection. It is a recalibration of what’s already happening—and what the market has yet to recognize.

Intro: Beyond the Deck, Beyond the Floor

Across seven articles—Billion Dollar Layup, Beyond the Salvage Floor, IL-2 Viral Control and Cold Tumor Crackup, Beyond Resistance, The Next Layer, Confidence in Layers , The Biomarker Mosaic—we mapped, validated, and re-weighted MDNA11’s valuation in the context of its known development plan and laid the foundation around how that is just the beginning. We refined floor confidence, aligned PRISM-11 logic with Medicenna’s corporate disclosures, and updated our models using composite biomarker logic and mechanistic response data.

But those initial articles, while comprehensive, were built around declared clinical intentions. They reflect Medicenna’s roadmap and the conservative assumptions we made when modeling the $2.69B–$3.25B NPV floor. They explain what MDNA11 is doing. They do not yet explain everything it could do. The market, understandably, values what it sees.

But that leaves a substantial category unmodeled: scientifically grounded, mechanistically justified combinations that are translationally sound—but not yet declared.

These are the combinations that don’t show up in the April 2025 corporate deck. They weren’t reflected in Beyond the Salvage Floor. And they’re absent from standard Wall Street models (if those even exist which I doubt). But if you’ve read the translational literature, if you’ve studied the immune system’s failure patterns, and if you’ve followed the trail of MDNA11’s IL-2’s selective βγ signaling advantages—then these combinations don’t read as speculative. They read as logical extensions of what is already working.

This article doesn’t propose moonshots. It proposes adjacencies: combinations where the biology is validated, the rationale is robust, and the NPV impact is nontrivial. The goal is not to overextend. The goal is to connect the dots the market hasn’t yet priced.

We present six PRISM-11–projected combination strategies—none of which were featured in Medicenna’s April 2025 investor materials, and none of which were modeled in Beyond the Salvage Floor. But each is grounded in peer-reviewed data. Each expands MDNA11’s reach in cold tumors, immune-inert TMEs, and checkpoint-insensitive contexts. And each—when layered over our current confidence-tiering—justifies an additional $1.3–$2.1 billion in unmodeled valuation.

These are the combinations that shift MDNA11’s potential from floor to frontier.

PRISM-11 Combo Expansion Breakdown

Each of the six combinations below is grounded in peer-reviewed research. The table outlines their translational basis, confidence tiers, and unmodeled NPV uplift potential. But numbers alone don’t tell the story. Each strategy below is expanded in detail to show why it matters, how it fits, and what the upside is.

1. MDNA11 + Radiotherapy (TREM1⁺ Monocytes)

This strategy is built around findings from Wang et al. (2025), who showed that short-course radiotherapy followed by neoadjuvant immunotherapy induces a TREM1⁺ CCR2⁺ monocyte population that promotes CD8 T cell priming, dendritic co-stimulation, and long-term IFNγ signaling. This TREM1-high MoMac signature was predictive of better pathological response and DDFS, and interestingly, was linked to upregulation of IL-2–related pathways.

This is precisely where MDNA11 operates. A radiotherapy-primed microenvironment expressing TREM1 and IFNγ-related cytokine programs is not just receptive—it’s optimized for MDNA11’s βγ-selective IL-2 engagement. The biology doesn’t need to be changed—it needs to be extended.

In tumors like LARC, MSS CRC, and select pre-surgical NSCLC subsets, the RT + IL-2 combo could shift complete response rates while avoiding checkpoint toxicity. This isn’t speculative—this is mechanistically ready. And it’s already been glimpsed in real-world settings. One of the earliest reported near-complete responses (PR) in the MDNA11 trial occurred in a patient with pancreatic ductal adenocarcinoma (PDAC). This patient achieved a deep PR over a year in treatment. This patient was on death’s door when they entered the trial. At approximately 55 weeks in, the patient, given a new lease on life, decided to go on an extended holiday – 7 weeks! Upon returning, they got back on treatment but a new lesion was discovered and received a single cycle of stereotactic body radiotherapy (SBRT), and then got back on MDNA11again. That patient’s disease trajectory—marked by durable tumor shrinkage and functional stability—suggests that even limited RT exposure may have primed the tumor microenvironment for further βγ-selective IL-2 engagement. It reinforces the TREM1-linked radiotherapy signature observed by Wang et al. and positions RT + MDNA11 as a translationally validated, clinically testable strategy in cold or fibrotic tumors.*At 84 weeks, this patient was deemed in remission and this was confirmed at week 150.

2. MDNA11 + NP-Dox + Vaccine

This strategy builds on findings from Chen et al. (2025), who demonstrated that liposomal doxorubicin (NP-Dox) pre-treatment enhances the immunogenicity of tumor-derived membrane vesicles used in nanovaccines. NP-Dox upregulates MHC-I expression, increases dendritic cell antigen processing, and facilitates durable CD8+ T cell priming. Tumor lysates collected after NP-Dox exposure led to superior vaccine efficacy compared to those generated post-surgery or using untreated tumor cells.

This dovetails with MDNA11’s IL-2–driven reprogramming. Where NP-Dox expands antigenicity and improves antigen visibility, MDNA11 ensures that cytotoxic T cells are sustained, not exhausted. In immune-desert settings (e.g., TNBC or PDAC post-chemo), the combination creates a two-stage logic: expose the tumor, then rewire the T cells. The concept is not abstract—it’s an extension of a vaccine-antigen priming model that’s already being tested in multiple solid tumor indications. Adding MDNA11 could be the link that turns partial responses into durable memory.

3. MDNA11 + EGFR mAb + HER2-ADC

This combination draws from the findings of Gupta et al. (2024), who showed that EGFR overexpression in EGFR⁺/HER2⁺ tumors can suppress ADC internalization—rendering therapies like trastuzumab deruxtecan (T-DXd) less effective. When EGFR-directed monoclonal antibodies such as cetuximab or panitumumab were introduced, internalization was restored, payload delivery resumed, and tumor control improved. This rescue mechanism offers a compelling opportunity for combination with MDNA11.

Here’s why: many cold tumors (especially HER2⁺ CRC, PDAC, and NSCLC) suffer from both checkpoint resistance and ADC resistance driven by EGFR-mediated barrier effects. MDNA11’s role here is not to replace checkpoint therapy—but to sustain and amplify cytotoxic effector function in the post-ADC, post-EGFR neutralization phase. It converts partial trafficking into complete immune memory. By pairing EGFR blockade with HER2-targeted ADCs and MDNA11-driven βγ IL-2 reprogramming, this combination could unlock high-value subpopulations that today remain invisible to monotherapy modeling.

None of these were modeled in Beyond the Salvage Floor. Each expands the floor logic without double-counting current Medicenna-disclosed indications. These combinations target immune deserts, cold tumors, and barrier-locked tumor microenvironments—each offering a different window into IL-2–mediated rewiring.

4. MDNA11 + IL-21 (Stemness Rescue)

Rubino et al. (2024) demonstrated that IL-21 signaling via IL-21R reprograms leukemic stem cells in AML by suppressing the MYC/p38 MAPK/ROS axis, promoting asymmetric division, and enhancing response to both chemo and CAR-T therapy. This immune-stemness logic doesn’t just apply to hematologic malignancies—it informs our understanding of T cell exhaustion in solid tumors, especially where terminally exhausted (TexTerm) cells dominate.

MDNA11’s role in stem-like CD8 re-expansion is already supported by Tpex → TexProg lineage tracking. When paired with IL-21, this combination could target both immune and tumor-side stemness—shifting effector exhaustion states while rebalancing metabolic stress loops. This is particularly important in PDAC, NSCLC, and ovarian tumors with MYC-driven resistance or metabolic lockouts. We aren’t inventing new biology—we’re synchronizing known circuits.

5. MDNA11 + BiTE/CD3 Therapy

BiTEs (bispecific T cell engagers) and CD3-targeted synthetic immunotherapies are known to generate rapid—but often fragile—T cell activation in MHC-I-deficient or immune-desert tumors. What they gain in specificity, they often lose in durability. MDNA11 may be the bridge.

PRISM-11 modeling identifies several tumor types (e.g., AML, prostate, neuroendocrine tumors) where checkpoint blockade has failed and where MHC-I loss or low neoantigen burden makes T cell recruitment ineffective. In these contexts, BiTEs can provide specificity—but not memory. MDNA11, by sustaining βγ-driven effector proliferation and IFN-γ signaling, could preserve the activity initiated by BiTEs and convert it into meaningful tumor control. This is particularly relevant in tumors where CAR-T has struggled and where checkpoint combo trials have failed.

The logic isn’t speculative—it’s synthetic. And the combination may be one of the most scalable IL-2 triplet strategies not yet modeled.

6. MDNA11 + Endocrine + PD-1 (ER⁺ Breast Cancer)

Chen et al. (2025) demonstrated that hormone therapy—specifically a combination of a GnRH agonist and the aromatase inhibitor exemestane—significantly enhances the efficacy of anti–PD-1 immunotherapy in premenopausal women with ER⁺/HER2⁻ breast cancer. The study showed that endocrine suppression reshaped the tumor microenvironment, reduced immunosuppressive signaling, and enabled a meaningful increase in CD8⁺ TILs and IFNγ signaling.

For MDNA11, this presents a rational combination: endocrine therapy clears the immunologic brush, checkpoint blockade reactivates cytotoxic T cells, and MDNA11 amplifies and stabilizes the effector wave through IL-2Rβγ signaling. It’s a triplet that combines microenvironment remodeling, checkpoint unlocking, and cytokine-driven reprogramming—each aligned in timing and purpose. ER⁺ tumors have long been checkpoint-inert, and this strategy shows that cold tumors aren’t unresponsive—they’re unprepared. MDNA11 may help change that.

Together, these six rational but undeclared combinations suggest that MDNA11’s value—if pursued strategically across immunologic failure modes—may exceed its modeled floor by more than $1.3B–$2.1B, independent of new TAMs or pricing assumptions. These are not speculative shots in the dark. They’re the product of targeted scientific synthesis—where known translational pathways converge with MDNA11’s design to generate actionable therapeutic logic.

Summary Callout: A Valuation Horizon, Not a Ceiling

None of the combinations outlined here are modeled in Medicenna’s April 2025 corporate presentation. None are reflected in Beyond the Salvage Floor’s $3.25B floor. But all are translationally grounded. All are strategically actionable. And all point to one conclusion:

PRISM-11’s forecast isn’t just conservative—it may be structurally incomplete.

This is not a call to inflate TAM or overextend indications. It’s a recognition that reprogramming agents like MDNA11 create new surface area: in checkpoint-inert settings, in stroma-rich tumors, in memory-excluded niches. That surface area isn't priced in yet—but it should be.

What happens when you stop modeling what’s disclosed—and start modeling what’s biologically inevitable?

You move from modeling valuation ceilings to modeling valuation reach.

So I’m sorry to bore you with all this science—brick by brick, cytokine by cytokine—just to say what the market keeps missing: MDNA11’s Net Present Value isn’t ~$10/share as a salvage-only asset. It isn’t even ~$25–30/share as a composite-reweighted checkpoint rescue and biomarker-selected agent.

Based on what I’ve uncovered to date—grounded entirely in peer-reviewed translational research and mechanistic modeling—it’s more likely a $4.5B–$5.4B platform, or $43–51 per share, assuming ~105M fully diluted shares.

That figure includes nothing speculative—no new tumor types, no unapproved modalities, no blue-sky pricing assumptions. It’s a reweighting of reality, where each node of translational insight becomes an unlock. From TREM1 priming and liposomal vaccine antigenicity, to IL-21-driven exhaustion rescue and BiTE/CD3 anchoring—these aren’t moonshots. They’re what happens when a best-in-class IL-2 superkine meets biology that’s already bending.

And that’s before anyone else connects the dots.

📚 References

Wang X, et al. (2025). Preclinical study and Phase 2 trial of neoadjuvant immunotherapy for locally advanced rectal cancer. Cell. https://doi.org/10.1016/j.cell.2024.04.017

Chen X, et al. (2025). Neoadjuvant chemotherapy by liposomal doxorubicin enables tumor-membrane-derived personalized nanovaccines. Nat Biomed Eng. https://doi.org/10.1038/s41551-025-01150-5

Gupta M, et al. (2024). EGFR-directed antibodies promote HER2-ADC internalization in resistant EGFR-overexpressing tumors. Nat Cancer. https://doi.org/10.1038/s41571-024-00895-z

Rubino C, et al. (2024). IL-21–IL-21R signaling renders AML stem-like cells responsive to chemotherapy and immunotherapy. Blood. https://doi.org/10.1182/blood.2022019087

Chen Y, et al. (2025). Hormone therapy enhances anti–PD-1 efficacy in premenopausal ER-positive breast cancer. Nat Med.

Postscript: From $60 Million to “You’ve Got to Be Kidding Me”

This entire series began before I knew what it would become. I just knew one thing: Medicenna’s ~$60 million market cap—post-Confidence Intervals—was absurd.

We can rationalize how it happened: biotech’s macro malaise, 1–3 year funding horizons, the usual baby-and-bathwater routine. But let’s not ignore the third rail: malicious market structure and actors who prey on underfunded biotechs until they’re cornered into bad options or worse deals. That part of the story is coming too.

It started with seeing if MDNA11 could justify a valuation under the narrowest of lenses—built only on salvage data, scientific quantification, and a sober sense of probability. That’s where we started. And maybe, if we were lucky, Medicenna could license itself out of obscurity with MDNA11, or MDNA113, or both.

Last Monday, I made the conservative case for ~$10/share.

By Friday, we’d argued our way to a $2.6 billion valuation floor.

And now? We’ve stepped over $5 billion—without touching blue-sky pricing, new tumor types, or population inflation. Just trial-confirmed immunology, composite biomarker logic, and thirteen rational combination strategies no one else has modeled.

This isn’t blind optimism—it’s Confidence Intervals, operationalized. We’re targeting immune deserts, checkpoint-inert tumors, and failure modes that current trials can’t reach. We didn’t inflate TAM. We weighted it correctly.

The same cohort-level probability modeling that held in earlier immunotherapy waves—where PD-1 agents outperformed early expectations due to layered immune repair—applies here. It’s surface-area expansion. The only thing being cannibalized is every lazy model still pretending IL-2 died with aldesleukin.

So if $5 billion sounds aggressive, I’d agree—if I hadn’t just spent eight articles showing why it’s conservative.

This isn’t hype. It’s immune topology, priced in advance. PRISM-11 just formalizes it. We are pricing confidence before the market does.

Unfortunately, I’m not the first person outside of Medicenna to see this potential. Someone else sees it too—but didn’t bet on approval, or science, or optionality. They are betting on illiquidity, disinterest, and time decay. I don’t know who they are. But there is a malicious actor or firm who’s positioned not to win if MDNA11 fails—but to profit if it’s starved.

That’s not short selling. That’s system gaming. And this valuation arc wasn’t just about proving the science—it was about making that game harder to play. I know what they’re doing between the TSX and the OTC. Unfortunately for them, I also know the real float is a fraction of the outstanding shares—because I know who’s holding, and how long they’re willing to wait. And if this firm or shop think they can outlast that… they’ve mispriced more than the science.