REFERENCE TO A SEQUENCE LISTING SUBMITTED AS A TEXT FILE VIA EFS-WEB

The official copy of the sequence listing is submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file named 513988SEQLIST_ST25.TXT, created on May 17, 2018, and having a size of 1,254 bytes and is filed concurrently with the specification. The sequence listing contained in this ASCII formatted document is part of the specification and is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The subject matter contained herein relates generally to antigen-capturing nanoparticles (AC-NP), their formation and use in the treatment of cancer.

BACKGROUND

Cancer immunotherapy, the utilization of the patient's own immune system to treat cancer, has emerged as a powerful new strategy in cancer treatment. Recent development of antibodies that can block negative immune regulatory pathways, such as the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1), have resulted in clinical improvements in patients with melanoma that was not seen previously. Although much of the initial focus of immunotherapy has been in patients with melanoma, growing evidence suggests that these therapeutics are effective in many other malignancies. Anti-CTLA-4 (αCTLA-4) and anti-PD-1 (αPD-1) treatments are being investigated in prostate, lung, pancreatic, bladder, renal cell, and head and neck cancers. Early clinical data suggest immunotherapy will make major impacts on these diseases as well. A major limitation of cancer immunotherapy is the low response rate. Treatment with either single agent (αCTLA-4 or αPD-1) or combination treatment results in response rates of 10-40%. Patients who do respond to these treatments have prolonged survival. Such findings have led to high interest in developing strategies to further improve cancer immunotherapy. The current cancer immunotherapy utilizing patient's tumor cells generally utilize tumor cell lysates and/or the patient's dendritic cells. But the response rates as well as the effects are low.

A different clinical approach of substantial interest to improving immunotherapy has been to combine radiotherapy with the use of immunotherapy agents. Radiotherapy has been shown to enhance immunotherapy, especially in generating the abscopal effect, a phenomenon in which local radiotherapy leads to systemic regression of metastatic cancer. First reported in the 1950's, the abscopal effect is a rare event that has been reported in patients with melanoma, renal cell carcinoma, and lymphoma. Preclinical data suggest that the abscopal effect can be enhanced by combining radiotherapy and other immunotherapy modulations. Postow et al. validated such preclinical data recently in the New England Journal of Medicine by demonstrating an abscopal effect in a patient with metastatic melanoma. Treatment regimens that can lead to the abscopal effect have the potential to turn the primary or metastatic tumors into tumor vaccines.

The mechanism of synergy between immunotherapy and radiotherapy is thought to be due to radiotherapy increasing the antigen exposure to the myeloid cells. Radiotherapy-induced cell death induces the release of many tumor antigens and enables the development of an antigenic “cascade” (expansion of T cell clones that are reactive against a variety of tumor antigens) rather than an immune response against a few antigens. This is critical to the success of immunotherapy in several ways. First, strongly immunogenic antigens are usually lost during tumor progression as tumors evade the immune system, making it difficult to select specific antigen targets. Second, past experience with cancer vaccines has demonstrated that eliciting an immune response against one or several “chosen” tumor antigens does not result in improved cancer survival. Furthermore, activation and expansion of T cells specific for the tumor antigen present in a cancer vaccine failed to correlate with tumor response in clinical trials. Such results suggest that T cells recognizing one or a few antigenic targets will have difficulty in achieving major therapeutic effects. Effective immunotherapy may rely on the immune system to recognize a multitude of antigens or antigenic cascades. Radiotherapy is known to promote this antigenic cascade. Radiotherapy can also induce the release of immune modulating molecules that can further enhance immunotherapy. For example, radiotherapy can cause the release of alarmins, endogenous molecules that can activate the immune system from dying tumor cells. One particular alarmin released by radiotherapy, HMGB1, is known to induce maturation of dendritic cells (DCs) to promote a cytotoxic T-lymphocyte response through cross presentation of tumor antigens.

Separately, a key preclinical strategy to improve antigenic response is to utilize nanoparticles to improve antigen presentation and immune response. Nanoparticle bound antigens have been shown to elicit greater immune response than free antigens. Recently, Fadel et al. demonstrated that a carbon nanotube-polymer composite could activate T-cells in immunotherapy. Moreover, data suggest that immune responses to nanoparticles can be modulated by adjusting nanoparticle size and shape. Thus far, nanoparticle based immunotherapy strategies have involved selecting and combining several known antigens with nanoparticles. As mentioned above, such strategies may not generate a therapeutic response for the same reasons that cancer vaccines have failed. The nanoparticles disclosed herein are efficient at presenting tumor generated antigens to immune cells. The data described herein show an enhanced immune therapy in tumors.

BRIEF SUMMARY

One aspect of the subject matter described herein is directed to antigen-capturing nanoparticles and to methods for preparing the antigen-capturing nanoparticles.

Another aspect of the subject matter described herein relates to methods of treating cancer comprising administering the antigen-capturing nanoparticles to a subject in cancer immunotherapy. The method involves administering the antigen-capturing nanoparticles to a subject. The method further involves treating the subject with a cancer therapy, thus providing an enhanced cancer immunotherapy.

In an embodiment, the subject matter described herein is directed to antigen-capturing nanoparticles comprising a core covalently bound to a peptide which is covalently bound to PEG.

In another embodiment, the antigen-capturing nanoparticles contain an adjuvant.

Another embodiment involves a method for making the antigen-capturing nanoparticles.

Still another embodiment involves methods of using the antigen-capturing nanoparticles.

Still further embodiments are described as herein.

