Project 3 Successor: Combining Radiation Therapy and NKTR-214 to Elicit in Situ Tumor Vaccination in Head and Neck Cancer

Summary:

We are developing a new approach for the treatment of metastatic or recurrent head and neck cancers. We will utilize radiation therapy to help the patient’s immune system to better recognize their cancer, and we will combine this with immune stimulating treatments to enable the patient’s immune system to destroy tumor cells anywhere in the patient’s body. We will test this combined treatment approach in mice and use biospecimens from a clinical trial in head and neck cancer patients to determine how the treatment works.

Specific Aims:

  • Aim 1: Determine whether the combination of RT and NKTR-214 may elicit enhanced in situ tumor vaccination and anti-tumor immune response in syngeneic murine HNC models compared to RT or NKTR-214 alone and test the capacity of this combination to enhance response to anti-PD-1 ICI in the presence or absence of tumor-specific mAb.
  • Aim 2: Evaluate immunologic correlates of treatment in select biospecimens from a phase II trial in which patients with metastatic/recurrent HNC are treated with RT, NKTR-214, and pembrolizumab.

Collaborator:

Image of Adam Burr, MD, PhD

Adam Burr, MD, PhD

Assistant Professor
Human Oncology

 

 

Learn more:

We are developing a combined modality therapeutic approach to eradicating metastatic or recurrent head and neck cancers, including those that are immunologically “cold” and do not respond to immune checkpoint inhibition. Using an “in situ vaccine” regimen consisting of focal external beam radiation therapy (RT) and intratumoral (IT) injection of tumor-specific antibody (mAb) + IL2, we recently reported the ability to eradicate solitary, large, cold syngeneic tumors in mice. This in situ vaccine converts the targeted tumor into a focus of enhanced tumor antigen presentation, resulting in increased T-cell infiltration and potent T-cell memory. In that approach, we observed that repeated IT injection of IL2 was required for this in situ vaccine effect and intravenous (IV) delivery was not nearly as effective. This requirement for repeated IT injections poses a challenge for the clinical translation of this approach in metastatic or recurrent head and neck cancers. More recently, we have found that we can overcome this challenge using a PEGylated version of IL2, NKTR-214, which exhibits a prolonged half-life in serum compared to naked IL2 and which preferentially activates effector rather than suppressor T cells.

In preliminary studies, we have observed that RT + IV NKTR-214 elicits a potent in situ vaccine response without the need for IT injections. Building from this preliminary observation, here we propose to use syngeneic murine models of head and neck squamous cell carcinoma to systematically optimize the capacity of RT + NKTR-214 to elicit in situ vaccine and to evaluate whether this combination may augment response to anti-PD-1 checkpoint blockade. We will further test whether response to this combination may be enhanced by addition of the anti-EGFR antibody, cetuximab, which may enhance antigen presentation via Fc-receptor-mediated engagement of antigen presenting cells.

Finally, using blood and tumor biopsy specimens from patients enrolled in a separately funded phase II clinical trial, we will evaluate for immunologic correlates of treatment response to combined RT, NKTR-214, and anti-PD-1 therapies in patients with metastatic or recurrent head and neck squamous cell carcinoma. The results derived from these exploratory correlative studies on biospecimens will guide the rational design of correlative studies in subsequent advanced phase clinical studies (outside the scope of this award) testing the efficacy of combining RT, NKTR-214, and anti-PD-1 therapies in patients with metastatic or recurrent head and neck squamous cell carcinoma.

  • Aim 1: Determine whether the combination of RT and NKTR-214 may elicit enhanced in situ tumor vaccination and anti-tumor immune response in syngeneic murine HNC models compared to RT or NKTR-214 alone and test the capacity of this combination to enhance response to anti-PD-1 ICI in the presence or absence of tumor-specific mAb.
  • Aim 2: Evaluate immunologic correlates of treatment in select biospecimens from a phase II trial in which patients with metastatic/recurrent HNC are treated with RT, NKTR-214, and pembrolizumab.