APPENDICURE

A new preprint from researchers at Wake Forest School of Medicine and the Wake Forest Institute for Regenerative Medicine introduces a different way of thinking about immunotherapy in peritoneal cancers….including appendix cancer.

The work was led by investigators including Dr. Konstantinos I. Votanopoulos (Surgical Oncology), Dr. Shay Soker (Regenerative Medicine), and Dr. Adam R. Hall (Biomedical Engineering), with collaboration across oncology, cancer biology, and organoid research at Wake Forest. Here is the original article: Enhancing Patient Lymphocyte Response to Peritoneal Malignancies Using a Personalized Immunocompetent Microfluidic Co-Culture Platform

This is not a clinical trial.

It is not a treatment available today.

But it directly addresses one of the biggest barriers in appendix cancer immunotherapy — and that alone makes it worth understanding.

The Immunotherapy Problem in Appendix Cancer

Whether we are talking about:

• LAMN
• HAMN
• Mucinous adenocarcinoma
• Signet ring cell
• Goblet cell adenocarcinoma

Appendix cancer has historically been described as “non-immunogenic.”

Checkpoint inhibitors rarely produce meaningful responses.
Tumor-infiltrating lymphocyte (TIL) therapy requires immune cells already present inside the tumor.
And peritoneal tumors are often fibrotic, mucin-heavy, and immune-excluded.

In this Wake Forest study, researchers even note that in a significant portion of patients, TILs could not be successfully isolated at all.

That reflects the biology many of us understand too well.

So the investigators asked a different question:

If immune cells aren’t naturally infiltrating the tumor…
Can we train them outside the body?

What Wake Forest Built: A “Tumor-on-a-Chip” Training Platform

This takes be back to my professional experience – I’ve worked in B2B Tech my entire adult life and have always known sooner or later technology would play a significant role in finding new treatments and cures for cancer.

The team at the Wake Forest Organoid Research Center in Winston Salem, NC developed a microfluidic co-culture device – essentially a lab-based system that recreates aspects of the tumor microenvironment.

During cytoreductive surgery CRS), they collected:

• Tumor tissue
• Peripheral blood
• Lymph node or spleen tissue

The patient cohort included:

• Low-grade appendiceal mucinous neoplasms (LAMN)
• Higher-grade mucinous adenocarcinoma
• Signet ring cell features
• Goblet cell adenocarcinoma
• Peritoneal mesothelioma

Blood-derived immune cells (PBMCs) were circulated through a chip containing the patient’s tumor cells and antigen-presenting cells for seven days.

Those blood cells were “trained” through repeated exposure to tumor antigens.

The resulting population was called Organoid Interacting Lymphocytes (OILs).

Did It Work in the Lab?

In ex vivo cytotoxicity testing against patient-matched tumor cells:

• OILs induced significantly more tumor cell death than TILs.
• OILs induced significantly more tumor cell death than blood cells expanded without tumor exposure.
• Mean tumor cell death:
  • OILs: 52.2%
  • Expanded PBMCs: 35.9%
  • TILs: 24.9%

Importantly, the paper explicitly describes appendiceal tumors as generally “non-immunogenic,” yet these trained immune cells still demonstrated activity.

That is not something we see often in appendix cancer research.

Why This Could Be Relevant Across LAMN, HAMN, Signet Ring, and Goblet

This was not a single-subtype experiment.

The patient table (pp. 39–43 in original article) shows representation across:

• Low-grade tumors
• High-grade tumors
• Signet ring cell features
• Goblet cell adenocarcinoma

The platform was tested across heterogeneous appendix cancer biology — the very heterogeneity that often limits immunotherapy success.

While this remains laboratory data only, the approach was not restricted to one grade or histologic subtype.

What Made the OILs Different?

The Wake Forest team identified several mechanistic differences:

Increased CD8+ Effector Cells

OILs showed enrichment of cytotoxic CD8+ T cells compared to baseline blood cells.

Increased Polyfunctionality

Single-cell cytokine profiling demonstrated more polyfunctional CD8+ cells. This means individual cells produced multiple effector cytokines simultaneously.

Polyfunctionality is associated with stronger antitumor responses in multiple cancer immunotherapy studies.

Granzyme A Upregulation

Spatial proteomic analysis showed significant upregulation of Granzyme A in OIL-treated tumor interactions, along with PARP-1 changes in tumor cells consistent with DNA damage pathways 2026.02.19.706377v1.full.

That suggests active cytotoxic signaling, not just immune presence.

A Potential Predictive Marker

Interestingly, the study identified that patients with lower baseline HLA-DR expression on circulating CD45+ cells were more likely to benefit from the tumor-on-chip training platform.

This raises the possibility that immune profiling could help determine who might benefit most from this strategy.

What This Means and What It Doesn’t

This is:

• A preprint (a complete draft version of a scientific manuscript shared publicly online before it undergoes formal peer review)
• Ex vivo laboratory data
• Early-stage platform research

It is not:

• A completed animal study
• A human clinical trial
• An approved therapy

But conceptually, this work from Wake Forest addresses a central immunotherapy barrier in appendix cancer:

• The lack of tumor-infiltrating immune cells.
• Instead of depending on what the tumor already contains, this platform attempts to build tumor-reactive immunity from peripheral blood.

This is significant.

Why Should I Watch This

Appendix cancer has repeatedly been categorized as immunologically “cold.”

This research suggests that cold tumors may NOT be unreachable, if immune cells are trained properly.

There is still a long road from preprint to patient treatment.

BUT this platform, developed by a multidisciplinary team at Wake Forest in Winston Salem, NC spanning surgical oncology, regenerative medicine, cancer biology, and biomedical engineering. represents one of the more technically sophisticated attempts to solve the immunotherapy problem in peritoneal disease.

For the rare cancer community, that is worth following carefully.