First Look: Block II

Session Focus

Rexrode opened the second half noting how impressive the first session had been. The same format applied: six presentations, each closing with a specific partnership or investment ask.

An Engine to Turn Brain-Immune Communications into New Medicines for Depression — Michael Wheeler PhD

Rexrode introduced Wheeler as a Rappaport Mass General Brigham research scholar in the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and assistant professor of neurology at Harvard Medical School, whose lab showed that chronic stress pulls inflammatory immune cells toward the brain’s fear center and that interrupting those cells reverses both the inflammation and the behavior.

Depressive episodes affect more than 20 million Americans annually, over 10 million of them severe, with roughly $20 billion spent globally each year on medicines alone. Current treatment fails approximately one third of patients, and Wheeler’s explanation is that most therapies conventionally target synaptic transmission and neurons, leaving other biology untreated.

The clinical clue came from patients with comorbid depression treated with immunosuppressive drugs, who showed long-lived improvements in mood.

Using animal models of psychological stress that recapitulate cellular, molecular and circuit features of depression, the lab found that chronic stress sends inflammatory immune cells from the body to the meninges. There they release pro-inflammatory cytokines acting on brain-resident cells including astrocytes, which facilitates astrocyte communication with neurons and drives activation of stress-promoting circuits and behavioral dysfunction.

Specifically, innate cytokines including IL-1 beta, TNF alpha and IL-12 are upregulated in the plasma of chronically stressed mice, alongside increased recruitment of pro-inflammatory monocytes and neutrophils to the meninges.

Inflammation behaves as a rheostat rather than a switch. Adoptively transferring more inflammatory immune cells into chronically stressed mice exacerbates stress-related behavior; acutely depleting the cells reaching the brain reduces it.

The finding holds in human samples. Treating human astrocytes with the cytokines detected in stressed mice induces the same inflammatory mechanisms. Profiling brains of individuals with major depressive disorder identified a depression-associated astrocyte subset marked by increased inflammatory responses, validated in patient tissue.

The therapeutic clue was unexpected. Transcriptional analysis of the immune cells reaching the meninges showed decreased serotonin receptor signaling alongside expression of serotonin receptors. Those receptors bind psychedelic compounds as well as serotonin, and psychedelics are arguably the most important psychiatric therapy for depression in a quarter century, with a single dose producing mood improvements lasting months.

Administering psilocybin or MDMA to chronically stressed animals reversed the recruitment of pro-inflammatory immune cells to the meninges, with behavioral rescue consistent with human patient observations and concomitant with the change in inflammatory burden.

That yields a patent-pending platform: identify targets activated in both the brain and peripheral immune system under chronic experimental stress, functionally filter for valid targets, screen behaviorally in living animals, and validate in clinical samples. The platform has identified dozens of targets convergent between brain, immune system and psychedelic therapy, and applies to any disorder involving brain and immune dysfunction including anxiety and addiction.

The goal is non-hallucinogenic psychiatric agents producing the same mechanisms as psychedelics while acting on peripheral immune cells rather than the brain directly.

The ask: a partner and $1 to $2 million to develop the first chemical matter in conjunction with the Mass General Brigham translational arm.

Trojan Horses — Jennifer Guerriero PhD

Rexrode introduced Guerriero as a lead investigator in the Division of Breast Surgery at Brigham and Women’s Hospital, assistant professor of surgery at Harvard Medical School, and a 2026 Lloyd J. Old STAR of the Cancer Research Institute.

Immunotherapy has transformed cancer care, yet 80 percent of patients with solid tumors do not respond. Immunotherapy requires T cells within the tumor, and the Guerriero laboratory has been internationally recognized for showing that tumor macrophages potently inhibit T cell recruitment and activation, and that removing macrophages expands immunotherapy success.

Macrophages are dominant in the solid tumor microenvironment, representing up to 50 percent of some solid tumors. Despite that, no FDA-approved therapy targets them.

Identifying which macrophage to target required an exhaustive multi-omic approach across hundreds of solid tumors. Single cell RNA sequencing across hundreds of breast tumors identified 10 macrophage types, which the lab then characterized functionally, located spatially relative to T cells and cancer cells, and correlated with survival.

TREM2-positive macrophages emerged as the target. They correlate with poor clinical response, inhibit T cell recruitment and promote metastasis. They are found across most solid tumor types and have limited expression in normal tissue, making this a pan-cancer and cancer-specific target.

The challenge was how to drug it. TREM2 antibodies have been tested preclinically and clinically, but antibodies have limited penetration and persistence in solid tumors, and a phase one TREM2 antibody trial failed on efficacy. CAR-T and CAR-NK approaches have revolutionized blood cancers with limited success in solid tumors, again because those cells struggle to reach the tumor.

Monocytes do not. They rapidly and efficiently penetrate and persist within tumors, and CAR-monocytes have been tested in phase one with a favorable safety profile.

The approach engineers patient monocytes with a TREM2 CAR. Infused, they rapidly infiltrate solid tumors, precisely identify and eliminate TREM2-positive macrophages, and permit T cell infiltration, activation and tumor elimination.

In a murine breast cancer model, TREM2 CAR-monocytes eliminated TREM2 macrophages in high numbers, produced a two to three-fold increase in tumor T cells and a 50 percent reduction in tumor burden as monotherapy. Combined with anti-PD-1, the model showed rapid tumor elimination and increased overall survival, where PD-1 alone had little efficacy.

The lead indication is triple negative breast cancer with a market opportunity above $1 billion, followed by ovarian and lung cancer, both highly infiltrated with TREM2-positive macrophages. The platform opportunity is universal solid tumor targeting, designed to work as monotherapy and in combination, with preclinical evidence that removing these macrophages enhances chemotherapy and immunotherapy.

The team has received more than $2 million in non-dilutive awards, completed proof of concept, identified the lead target, filed broad patents and spun out a company.

The ask: strategic partners and investors to move from lead product to IND-enabling studies and a planned first-in-human trial.

MR Probe for Fibrogenesis Visualization — Eric Gale PhD

Rexrode introduced Gale as an associate professor of radiology at Massachusetts General Hospital, the Martinos Center and Harvard Medical School, who applies chemistry to intractable biomedical problems, including molecular imaging probes to quantify chronic disease activity and treatments for anemia complicated by iron malabsorption in chronic kidney disease.

Fibrosis is the over-accumulation of scar tissue, an injury pathway common to many prevalent chronic conditions. Roughly half of people in the Western world are estimated to die of some form of fibroproliferative disease. The antifibrotic market is large, early and growing, with a substantial accompanying diagnostic market currently concentrated in chronic liver disease and beginning to expand.

The limitation of existing non-invasive markers is that fibrosis accumulates and resolves very slowly, making it a y-axis indicator of disease activity rather than a readout of what is happening now. Seeing fibrogenic mechanisms directly would provide intermediate information in long and expensive clinical trials, inform whether to initiate a therapy with severe side effects, and guide titration afterward.

The approach is molecular MRI, chosen because MRI provides excellent soft tissue resolution without ionizing radiation, which matters for a technology intended for repeated surveillance. The difficulty is that MR probes are detected with relatively low sensitivity compared to tracers, requiring an abundant molecular target and a probe engaging it with high specificity.

The fibrogenic microenvironment provides that target in allysine, a reactive amino acid generated transiently during collagen cross-linking, present at very high concentrations in fibrogenic tissue and very low abundance in normal tissue. Conjugating MRI probes to functional groups reacting with allysine produces delayed enhancement specific to that environment.

In an Alport mouse model of hereditary nephritis, a heterozygous mouse with normal kidney showed probe washout and little enhancement four hours after injection, while a littermate with active nephritis, renal fibrosis and active fibrogenesis showed strong conspicuous enhancement.

The practical obstacle is non-specific background from unbound probe, particularly in organs with excretory function. Four hours in a mouse converts to potentially days in humans, which is incompatible with high-throughput radiology workflows and with obtaining co-registered pre and post-injection images.

The solution is a biochemically activated probe generating no signal except within the pathologic environment. The lab discovered that iron complexes undergoing chemical oxidation switch from MR-invisible to conspicuously visible. The fibrogenic microenvironment is oxidizing, with an immunologic component: innate immune cells overexpress NADPH oxidase 2 activity, secreting large amounts of reactive oxygen species extracellularly.

In a unilateral ischemic kidney injury model imaged a day after injury, the probe turned on within two minutes, with signal concentrated in the outer stripe of the medulla where injury and inflammation were greatest. The probe clears roughly 85 percent through the kidneys, so the normal contralateral kidney was full of contrast but unenhanced, underscoring the on-off effect. Control studies confirmed sensitivity to oxidants generated downstream of immunological processes.

Seven days after injury, with inflammation largely resolved and active fibrogenesis underway, only the injured kidney enhanced within minutes.

Quantification held up. Immunofluorescent staining confirmed elevated allysine in injured kidneys with notable heterogeneity, and relative kidney signal enhancement correlated tightly with allysine proportional area, indicating the technology can quantify and dynamically monitor fibrogenic activity. The approach has been demonstrated in kidney and liver among other organs, and may show changes before conventional fibrosis biomarkers report, which can take months to years.

A strong lead has been identified with a composition of matter patent in process, and the regulatory path to first-in-human is well defined with substantial guidance available.

The ask: partners and roughly $10 to $15 million in full capitalization, which the team estimates would reach human studies in under two years.

Programmable Anticoagulants — Jonathan Carlson MD, PhD

Rexrode introduced Carlson as a hematologist-oncologist in the Mass General Cancer Center, Director of Chemistry at the Center for Systems Biology and assistant professor of medicine at Harvard Medical School, framing the problem as every drug preventing clotting also raising bleeding risk.

The fundamental challenge in hematology is that clinicians know what to do about clotting and what to do about bleeding, and patients can have both simultaneously, which occurs often in illness, trauma and critical care. Treating a pulmonary embolism is the right idea; anticoagulating a bleeding site is not. The bloodstream circulates continuously, making it impossible to medicate one location and not another.

The operating room presents the same problem in combined form. The cardiopulmonary bypass circuit is at critical risk of clotting and must be anticoagulated, while the patient is at risk of bleeding. Currently the field anticoagulates the machine while surgeons deploy an entire ecosystem of techniques to limit bleeding. Blood circulates the bypass circuit in about 20 seconds and the body in about a minute.

The team has spent years building chemical on and off switches. The critical element is a chemical scissors that cuts a molecule in half when it is no longer needed, or controls how long it lasts before cutting itself. Intravascular chemistry means no dependence on liver, kidney or protease, just chemistry in the bloodstream with no tissue, diffusion, monocytes or tumors involved.

The speed requirement is the hard part. Existing short-acting blood thinners last 10, 15 or 20 minutes to an hour. This requires seconds, a 500 to 1,000-fold acceleration in the rate at which the molecule metabolizes itself. Achieved, a medicine infused through a central line would erase itself during the seconds it dwells in the bypass circuit, anticoagulating the machine separately from the patient though both run continuously.

Feasibility was established in steps. First, can a switch be placed in an existing clinically approved anticoagulant? Four versions were made, all equipotent to the parent drug. Second, are both halves inert after cleavage? Each half proved completely inert, as did the two halves together, which matters since both are produced simultaneously.

The chemistry is tetrazine and trans-cyclooctene bio-orthogonal chemistry, which Carlson described as the preeminent molecular switch for fast in vivo chemistry because of the concentrations achievable. Progress since the concept was first published in 2013: reaction yield improved from 50 percent to 99 percent by 2018, complete cleavage now occurs in 30 seconds, and the reaction rate has improved five-fold, then 25-fold, and now 200-fold.

In vivo demonstration used red blood cells in a mouse ear. Labeled red cells were visible flowing through capillaries; adding the scissors on a second loop erased the signal in real time in circulating blood.

Clinical applications extend well beyond cardiac surgery, which is the clearest model of a machine anticoagulated at the patient’s risk. Critical care sees 5 million US ICU admissions annually, with simultaneous risks affecting renal replacement therapy and advanced life support. Dialysis anticoagulates machines at tremendous scale, with patients accepting the dose along for the ride.

Next steps are scaling up for testing on clinical samples at clinical scale, putting the chemistry into patient blood and clinical analyzers, with cardiac surgery as the critical model system, ready to begin testing once quantities and team are in place.

The ask: partners across cardiac surgery and critical care to advance these tools into clinical context.

Engineering SPARC-NK — Wilfredo Garcia-Beltran MD, PhD

Adoptive cell therapy has transformed cancer treatment with CAR-T at the forefront, reaching a $6 billion market value last year and success rates as high as 98 percent in certain blood cancer indications.

The limitations preventing broader scale are substantial: costs upward of half a million dollars per dose, systemic toxicity risk preventing first-line use, manufacturing delays because patient cells must be collected and engineered, essentially no accessibility outside tertiary centers, and the constraint that CARs reach only surface antigens with efficacy dependent on antigen density.

The lab’s response was to rebuild both the cell substrate and the receptor.

Natural killer cells were the natural substrate. They specialize in killing virus-infected and malignantly transformed cells, serve as first-line defense throughout life, can kill cancer cells never previously encountered, can be engineered to do so more potently, and have shown safety as an allogeneic off-the-shelf product with low toxicity across many trials.

Cord blood-derived NK cells have reached phase one and two trials showing genetically modified cells combating CD19-positive B cell cancers, but published studies show persistent manufacturing problems, with suboptimally manufactured products linked to suboptimal patient outcomes, a difficulty that has plagued the field.

One source has no manufacturing hurdles: an immortalized line called NK-92. It is infinitely renewable without a donor, permits multi-step engineering performed once then expanded at GMP scale for unlimited doses, allows tight product quality control not feasible with donor-derived products, and because it is delivered irradiated, dose can be controlled across a treatment cycle.

The reason it has not led the field is efficacy. Repeatedly shown safe when delivered into blood, brain or abdomen, it has not reproduced in vivo the efficacy seen in vitro. The lab’s finding was that the problem is the receptor: CARs were designed for T cells and do not provide sufficient signal for these cells to kill under irradiation.

That led to synthetic programmable antigen receptor complexes, or SPARCs, packaged into NK cells to target tumor antigens at the surface or inside the cell. The design takes the specificity and versatility of monoclonal antibodies and T cell receptors and grafts it onto the CD3 signal amplification complex, described as the most potent signaling receptor nature has produced, then packages that into NK cells for a safe, scalable product with high killing potency.

The first indication is relapsed refractory B cell cancers lacking the target antigens used by CAR-T and monoclonal antibody therapy, including plasmablastic lymphoma, which has poor outcomes, and B cell lymphomas relapsing after existing therapy. The antigen chosen was BCMA, targeted successfully in multiple myeloma and expressed at low levels in these other B cell cancers.

Results: substantial killing of a lymphoma line expressing moderate BCMA, greater killing against multiple myeloma cells expressing high BCMA as expected, and substantial killing across primary patient-derived lymphomas ranging from a 19-year-old with ALK-positive B cell lymphoma to a 52-year-old with plasmablastic lymphoma, in cases where no therapies were available to those patients.

Benchmarking used live-cell real-time imaging. Against CAR-T cells, SPARC-NK showed substantially greater killing. Against CAR-NK cells the killing was similar under standard conditions, but lowering the therapy cell dose and rechallenging with tumor cells showed SPARC-NK maintaining tumor control while CAR-NK eventually let tumors grow out. All of this occurs while producing considerably fewer inflammatory cytokines associated with systemic toxicity.

Platform breadth has been demonstrated against low mesothelin in cervical cancer, again outperforming CAR-T, with near-complete eradication of cervical cancer in the abdomen of mice in vivo. Intracellular and viral antigens are also targetable, including NY-ESO-1, expressed in gastrointestinal, gynecological and breast tumors, with breast cancer cells killed in vitro.

A patent application was filed the week before the presentation. Beyond cancer, the platform has clear application in autoimmunity, where the need for a safe cell therapy is now considerably greater.

The ask: partners with the interest, capability and experience to take cell therapies into the clinic, to execute final IND-enabling preclinical work, GMP-grade production and eventually clinical trials in roughly five years, both within the Mass General Brigham network and internationally.

The FNDC1-NAMPT-NAD* Axis — Rajeev Malhotra MD

Vascular calcification is the deposition of calcium phosphate crystals in the arterial wall. It can affect any artery and produces myocardial infarction, stroke and peripheral arterial disease, which remain the largest causes of morbidity and mortality globally despite LDL and triglyceride lowering therapies. No therapy targets calcification itself.

Malhotra described a CT scan from a patient he had cared for in the intensive care unit that weekend, a woman with critical limb ischemia, showing the aorta essentially filled with calcium: bone forming where bone should not be.

There are two forms. Intimal atherosclerotic calcification narrows the lumen and obstructs blood flow, producing infarction and stroke. Medial calcification of the middle vessel layer produces arterial stiffness, hypertensive heart disease and heart failure with preserved ejection fraction. Roughly 80 to 90 percent of calcification in both processes is mediated by the vascular smooth muscle cell, which is not terminally differentiated and can shift from a contractile to a bone-like osteogenic phenotype under stress.

Calciphylaxis is the most severe form, an accelerated calcification of skin vessels mainly affecting patients with end-stage renal disease on hemodialysis. There are roughly 35,000 to 70,000 new cases annually worldwide, producing painful necrotic skin lesions, and 50 to 80 percent of these patients die within a year of diagnosis from superimposed infection and sepsis. No approved therapies exist. Roughly 3.5 million people are on dialysis worldwide.

Mass General Brigham is a hub for calciphylaxis management, which enabled a large biobank of calciphylaxis tissue alongside large vessel disease samples. Spatial and single cell analyses identified FNDC1 as highly upregulated in calciphylaxis vascular tissue. What distinguished it from similar targets is that expression is also increased in coronary artery disease and peripheral arterial disease. Spatial analysis and immunohistochemistry localized it specifically to the vascular smooth muscle cell layer.

An extracellular isoform enters the circulation, which the team validated as a novel biomarker: two-fold upregulated in the blood of calciphylaxis patients, and a predictor of myocardial infarction and stroke in large cohorts including the UK Biobank.

Causality was established across multiple lines. In human vascular smooth muscle cells calcifying in culture, overexpressing FNDC1 induced calcification and inhibiting it suppressed calcification. Protein network analysis identified NAMPT, which synthesizes NAD, as a downstream target. As smooth muscle cells transition to a bone-like state they become highly proliferative and require increased cellular energy, and FNDC1 drives that by upregulating NAMPT. Inhibiting NAMPT completely blocked calcification induced by FNDC1 overexpression.

In vivo, FNDC1 levels rose in multiple murine models of vascular calcification. Global genetic deletion of FNDC1 produced mice with normal lifespans and health while inhibiting vascular calcification by more than 50 percent and improving survival. A small molecule inhibitor of the pathway produced similar reductions.

The strategic distinction matters. Bisphosphonates, calcium-based approaches and newer agents have failed in vascular calcification, in his assessment because they target the end stage, the actual deposition and extension of calcium crystals. This approach inhibits the earlier cell state transition. FNDC1 is not widely expressed across the body, tending toward vascular tissue, adipocytes and possibly skeletal muscle, which suggests a more specific avenue.

The work is supported by the MGB Amplify translational program. Multiple modalities have been evaluated, a team of development experts assembled, and efficacy assessments in in vivo models are planned for IND-enabling work.

The ask: co-investment or research collaborators to generate or optimize molecules for novel composition of matter and IP. Calciphylaxis is positioned as the entry point, with the same pathway relevant to calcification in end-stage kidney disease and peripheral arterial disease.

Key Takeaways

1. Chronic stress drives inflammatory immune cells to the meninges, and psychedelics reverse that recruitment, pointing to non-hallucinogenic immune targets for depression.

2. TREM2-positive macrophages are a pan-cancer target that antibodies cannot reach, while engineered monocytes infiltrate solid tumors readily.

3. An oxidation-activated iron probe images active fibrogenesis within minutes rather than after hours of clearance, with signal correlating to tissue allysine.

4. Bio-orthogonal chemistry can erase an anticoagulant in 30 seconds, allowing a bypass circuit to be anticoagulated separately from the patient.

5. Replacing both the cell substrate and the receptor let an off-the-shelf NK platform outperform CAR-T against low-antigen patient-derived lymphomas.

6. FNDC1 drives calcification through NAMPT, and blocking it cut calcification by more than half while improving survival in animal models.