July 1, 2018 (Vol. 38, No. 13)

To Fight Cancer More Effectively, Change the Battlefield … Pathway by Pathway, Cell by Cell

Tumorigenesis is to healthy tissue what xenoforming, or hostile terraforming, is to the planet. Both tumorigenesis and xenoforming are processes that alter the environment so that it may become less hospitable to its usual inhabitants, and more welcoming to that which is alien.

But while xenoforming is just science fiction—the inspiration for “alien kudzu,” “meat moss,” and other horrors—tumorigenesis is all too real.

In tumorigenesis, the world that is warred over is the tumor microenvironment (TME), which consists of nonmalignant cells and extracellular matrix elements that are curiously accommodating toward malignant cells. The TME becomes more alien, more a travesty of healthy tissue, as tumorigenesis proceeds, perverting cellular communications and suppressing immune defenses.

If tumorigenesis is to be slowed or reversed, the TME must be reclaimed and restored, piecemeal if need be, molecule by molecule, pathway by pathway, and cell by cell. TME components of the highest importance include immunoregulatory elements. If such elements could be manipulated rightly—if they could be subjected to “immunoforming”—they would rouse rather than suppress immune defenses.

Immunoforming was a key theme at “Targeting the Tumor Microenvironment,” a recent Cambridge Healthtech Institute conference. At this event, scientists shared the latest advances in understanding and manipulating the TME. For example, conference speakers and attendees discussed strategies for targeting TME components and reversing tumorigenesis, which is essentially a campaign to transform the body’s internal ecosystems so that they may serve destructive rather than life-sustaining processes.

The conference highlighted ecosystem restoration options such as:

  • Neutralizing semaphorin 4D, a transmembrane protein, to block its TME-sustaining functions, which include the restriction of immune-cell infiltration and activity at tumor margins.
  • Targeting the ubiquitin-proteasome pathway to deplete immunosuppressive regulatory T cells.
  • Using TME gene signatures to optimize therapies that incorporate chimeric antigen receptor–engineered T cells.
  • Developing agents to reoxygenate typically hypoxic malignant tissues.

Shifting the Immune Balance

One of cancer’s nefarious strategies is to manipulate host defenses to mask a tumor’s presence or to enhance immune suppression. To counter this strategy, scientists at Vaccinex are targeting semaphorin 4D (SEMA4D), a large cell surface antigen found on the resting T cell and overexpressed in a variety of tumor cell types. SEMA4D has been implicated in vascular growth, tumor progression, invasion, and immune cell regulation.

“SEMA4D is highly expressed at tumor margins, where it promotes immune suppression in the TME by restricting immune cell infiltration and immunoactivity,” noted Elizabeth Evans, Ph.D., one of the speakers at the conference and a vice president of preclinical research at Vaccinex. Dr. Evans offered this observation in a discussion devoted to target validation and prioritization.

SEMA4D regulates the migration and differentiation of cells, especially immune cells expressing its major receptors, plexin-B1 and plexin-B2. Company scientists found that antibody blockade of SEMA4D restores the ability of dendritic cells and cytotoxic T cells to migrate into the tumor, while simultaneously reducing the function of multiple immunosuppressive cell lineages in the TME.

“These coordinated changes in the tumoral immune context are associated with durable tumor rejection and immunologic memory in several murine carcinoma models,” asserted Dr. Evans. “Importantly, anti-SEMA4D treatment enhances the activity of co-administered immunotherapies, including immune checkpoint inhibitors, chemotherapy, and epigenetic modulating agents.”

These preclinical findings encouraged Vaccinex to initiate a clinical trial to evaluate the company’s pepinemab (VX15/2503), a humanized immunoglobulin G4 monoclonal antibody against SEME4D, in combination with Avelumab, an inhibitor of the immune checkpoint PD-L1, in non-small cell lung carcinoma (NCT03268057). This trial is being carried out in collaboration with Merck (Darmstadt), one of Avelumab’s developers.

Vaccinex’ preclinical collaborators included Antoni Ribas, M.D., Ph.D., and Siwen Hu-Lieskovan, M.D., Ph.D., researchers affiliated with the Jonsson Comprehensive Cancer Center. This research center is currently sponsoring a trial to evaluate pepinemab in patients with anti-PD-1/PD-L1 refractory melanoma (NCT03425461). In addition, a neoadjuvant trial is recruiting pancreatic and colorectal cancer patients to evaluate clinical and pathological responses to pepinemab in combination with PD-1- and/or CTLA-4-directed therapies (NCT03373188). Finally, a Phase I/II trial of pepinemab is recruiting pediatric patients with recurrent or refractory solid tumors, including osteosarcoma (NCT03320330).

According to Dr. Evans, pepinemab synergizes with other immunomodulatory agents to enhance antitumor responses. “Inhibition of SEMA4D,” she explained, “represents a novel therapeutic strategy to promote immune infiltration into tumors, reduce mesenchymal suppression, and enhance the antitumor effects of immunotherapy.”

Modulating Regulatory T Cells

Ubiquitination, which encompasses far-reaching signaling pathways, provides a key degradation mechanism for proteins. Furthermore, reversible protein ubiquitination regulates virtually all known cellular activities. Opportunistic tumors exploit this host system to support their survival and metastasis.

“Our company targets the ubiquitin-proteasome pathway to develop novel medicines for treating cancer, inflammation, and neurodegenerative diseases,” said Suresh Kumar, Ph.D., senior director and head of drug discovery at Progenra. The company has developed potent inhibitors of ubiquitin protease 7 (USP7), the most widely studied among the 100 deubiquitinating enzymes. “Recent investigations have demonstrated that USP7 is essential for regulatory T cell (Treg) function in that it regulates Foxp3 and Tip60, which together drive the development and maintenance of Treg cell lineage,” Dr. Kumar explained.

According to Dr. Kumar, since immune suppressive Tregs in the TME correlate with poor patient prognosis, depletion or impairment of Tregs is an attractive cancer immunotherapy: “Using our UbiPro™ platform, we have developed potent USP7 inhibitors that impair Treg functions and are efficacious in various syngeneic solid tumor models, especially for melanoma and for lung and colon cancers. We will be taking this into clinical studies to evaluate safety and efficacy.”

Many future cancer therapies may be based on small molecules, Dr. Kumar suggested. “The use of exceedingly expensive antibody-based immunotherapies consistently shows that only 20–30% of the patients respond to therapy,” he said. “We believe that small molecules can better tackle disease processes and solid tumors. The small molecule drug approach will likely change the landscape for checkpoint inhibition therapies.”

Optimizing CAR T-Cell Therapies

T cells equipped with engineered chimeric antigen receptors (CARs) have successfully navigated multicenter clinical trials. Now CAR-engineered T cells are beginning to enter clinical practice. Going forward, CAR T-cell treatments may be optimized through the evaluation of associated TME gene signatures, said Adrian Bot, M.D., Ph.D., vice president, translational sciences, Kite Pharma.

Although previous studies correlated clinical activity of CAR T cells with a range of blood biomarkers, a detailed assessment of how CAR T-cell treatments change the TME has been lacking. Recently, Kite Pharma scientists succeeded in identifying a TME gene signature that was related to CAR T-cell treatment. According to Dr. Bot, exploiting IL-15, in conjunction with modulating interferon-related pathways and TME checkpoints, could optimize CAR T-cell proliferative capability and produce more efficacious T-cell interventions.

Solving the “Last Mile” Problem

Reaching the end of the road to cure cancer means eliminating every last malignant cell. This is no small task, especially because tumors highjack a natural process that embryos use to evade the mother’s immune system…hypoxia. Both embryos and tumors feature an environment that restricts the laminar flow of oxygen.

“Hypoxia is a fundamental characteristic of tumor malignancy that underlies immune evasion and metastatic progression,” remarked Stephen Cary, Ph.D., co-founder and CEO, Omniox. “Typically, in a tumor environment there is a poor organization of blood vessels such that areas about 100–200 microns away are poorly perfused. Since oxygen perfusion usually ceases beyond 80 microns from blood vessels, these hypoxic areas adapt to survive. They promote immune tolerance by altering the recruitment and function of innate and adaptive immune effector and suppressor cells.”

Reversing tumor hypoxia could be therapeutic. “Reoxygenating the microenvironment could help restore normal tissue biology,” Dr. Cary declared. “The challenge, which no one has yet overcome, is how to get oxygen into the desired neighborhood safely. Our company has engineered a very high affinity oxygen carrier, OMX-4.80P, using a platform based on heme nitric oxide/oxygen (H-NOX) proteins.”

H-NOX proteins are a family of gas-sensing proteins in prokaryotes and higher eukaryotes. According to Dr. Cary, OMX-4.80P can accumulate preferentially in tumors through an enhanced permeability and retention effect and can release oxygen only in the presence of severe hypoxia. Oxygenating malignant tissue helps restore the body’s natural anticancer immune responses. “Another advantage,” Dr. Cary points out, “is that since radiation therapy relies on oxygen to damage DNA, treatment with oxygenating molecules such as OMX-4.80P can synergize with radiotherapies to enhance tumor treatments.”

Having successfully used the molecule as a single agent and in combination with immunotherapies in preclinical testing, Omniox is optimistic about its upcoming clinical trials, which are scheduled to begin next year. “Delivering oxygen deep into the hypoxic tumor microenvironment could become a cornerstone therapy against a wide range of solid tumors,” Dr. Cary suggested. “The goal is to go the last mile and eliminate every last cancerous cell.”

Tumors characteristically develop hypoxia, which drives immunosuppression and malignant invasion. Omniox is developing therapeutic compounds to oxygenate malignant tissue to restore the body’s anticancer defenses.

Modeling the Human Tumor Microenvironment

Cross-talk between a nascent tumor and infiltrating immune cells contributes to the creation of an immunosuppressive microenvironment that helps cancerous cells avoid host defenses. This deleterious cross-talk can be modified, however, to hinder tumorigenesis. The benefit of intervening in deleterious cross-talk is underscored by the success of checkpoint immunotherapies and the continuing rise of immuno-oncology, notes Paul Volden, Ph.D., field application scientist, Taconic Biosciences.

To improve translation of novel immuno-oncology therapies, Taconic focuses on models that enable reproduction of the human tumor microenvironment (TME) in a murine system. For example, Taconic’s super-immunodeficient CIEA NOG mouse® may serve as a foundation for next-generation NOG models. According to Dr. Volden, such models may express human cytokines to support dual engraftment of the most challenging patient-derived cancers and human immune cells.

With the help of the new cytokine-transgenic models, therapies targeting immunosuppressive tumor-associated macrophages can now be studied within a human tumor microenvironment (Ito et al. 2013. J. Immunol. 191(6): 2890–9). Human-specific antibody therapeutics that target natural killer cells can now be investigated in vivo, facilitated by NOG mice expressing human IL-15 (Hanazawa et al. 2018. Front. Immunol. 9: 152.) And as a first in any rodent model, patient responses to a microenvironment-derived immunotherapy have been reproduced using NOG mice expressing human IL-2
cytokine (Jespersen et al. 2017. Nat. Commun. 8(1): 707).

These examples illustrate Taconic’s approach to enabling TME research through next-generation humanized models. Models that reproduce the human TME can help researchers translate therapies that intervene in pathologic microenvironment interactions.


Taconic Biosciences, a leader in genetically engineered rodent models and services, enables customers to acquire, custom generate, breed, precondition, test, and distribute valuable research models worldwide. 

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