Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

@article{Singha2014TumorAssociatedHL,
  title={Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy},
  author={Netai C. Singha and Tara Nekoroski and Chunmei Zhao and Rebecca A Symons and Ping Jiang and Gregory I. Frost and Zhongdong Huang and H. Michael Shepard},
  journal={Molecular Cancer Therapeutics},
  year={2014},
  volume={14},
  pages={523 - 532}
}
Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA… 

Figures and Tables from this paper

Targeting the Tumor Stroma: the Biology and Clinical Development of Pegylated Recombinant Human Hyaluronidase (PEGPH20)

TLDR
Pegylated recombinant human hyaluronidase (PEGPH20) is a novel agent that degrades HA and normalizes IFP to enhance the delivery of cytotoxic agents and appears to be a predictive biomarker of response.

Human Hyaluronidase PH20 Potentiates the Antitumor Activities of Mesothelin-Specific CAR-T Cells Against Gastric Cancer

TLDR
It is demonstrated that sPH20-IgG2 can enhance the antitumor activity ofCAR-T cells against solid tumors by promoting CAR-T cell infiltration.

Role of hyaluronan in pancreatic cancer biology and therapy: Once again in the spotlight

TLDR
Current understanding of the role of HA in the progression of PDAC is summarized, possible therapeutic approaches targeting HA are discussed, and inhibiting HA synthesis/signaling or depleting HA in tumor stroma are discussed.

Remodeling the Tumor Microenvironment Sensitizes Breast Tumors to Anti- Programmed Death-Ligand 1 Immunotherapy.

TLDR
It is demonstrated pegvorhyaluronidase alfa increased the uptake of anti-programmed death-ligand 1 (PD-L1) antibody in HA-accumulating animal models of breast cancer, and the increased levels ofAnti-PD- L1 antibody were associated with increased accumulation of T-cells and natural killer cells, and decreased myeloid-derived suppressor cells.

Breaching the Castle Walls: Hyaluronan Depletion as a Therapeutic Approach to Cancer Therapy

TLDR
A pegylated form of recombinant human hyaluronidase PH20 (PEGPH20) has been deployed as a potential cancer therapeutic in HA-high tumors, where it can collapse this matrix by degrading the HA-assembled tumor extracellular framework, leading to tumor growth inhibition, preferentially inHA- high tumors.

Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment

TLDR
It is imperative for clinicians and scientists to understand tumor immunology, identify novel biomarkers, and optimize the position of immunotherapy in therapeutic sequence, in order to improve pancreatic cancer clinical trial outcomes.

Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

TLDR
An overview of several barriers in solid tumors that limit mAb uptake and distribution are provided and approaches that have been utilized to overcome these barriers in preclinical studies are discussed.

CAR-T Cells Hit the Tumor Microenvironment: Strategies to Overcome Tumor Escape

TLDR
This review provides a comprehensive overview of the key tumor intrinsic mechanisms that prevent an effective CAR-T cell antitumor response and the most promising strategies to prevent tumor escape to CAR- T cell therapy.
...

References

SHOWING 1-10 OF 57 REFERENCES

Therapeutic Targeting of Hyaluronan in the Tumor Stroma

TLDR
In preclinical animal models, enzymatic removal of hyaluronan is associated with remodeling of the tumor stroma, reduction of tumor interstitial fluid pressure, expansion of tumor blood vessels and facilitated delivery of chemotherapy, which leads to inhibition of tumor growth and increased survival.

Effective targeting of the tumor microenvironment for cancer therapy.

TLDR
Measurement of HA is a viable biomarker approach for predicting antitumor response in animal models to the HA-depleting agent, PEGPH20.

Targeting hyaluronic acid family for cancer chemoprevention and therapy.

Enzymatic Depletion of Tumor Hyaluronan Induces Antitumor Responses in Preclinical Animal Models

TLDR
The ability of PEGPH20 to enhance chemotherapy efficacy is likely due to increased drug perfusion combined with other tumor structural changes, and enzymatic remodeling of the tumor stroma with PEG PH20 to treat tumors characterized by the accumulation of HA.

Immune microenvironments in solid tumors: new targets for therapy.

TLDR
It seems reasonable to speculate that tumor progression could be effectively diminished by combining cytotoxic strategies with therapies that blunt protumor immune-based effectors and/or neutralize those that instead impede development of desired anti-tumor immunity, thus providing synergistic effects between traditional cytot toxic and immune-modulatory approaches.

Expression of Hyaluronan in human tumor progression

TLDR
The down regulation ofHA expression in tumor cells is associated with progression of tumor from well differentiated through poorly differentiated stage, despite the constant HA expression in the tumor associated stroma.

Hyaluronan in human malignancies.

Increased hyaluronan content and stromal cell CD44 associate with HER2 positivity and poor prognosis in human breast cancer

TLDR
The association between HER2 positivity and intense stromal HA staining indicates that HA could be one of the factors involved in the unfavorable outcome of HER2‐positive patients and suggests that HA in breast carcinoma cells and CD44 in stromAL cells may have clinical significance.
...