Agnostic Immunization by Immunogenic Cell Death

Cancer vaccines against defined tumor antigens in solid tumors have not worked well in patients because the host immune response is insufficient to reject established tumor.

Adoptive therapy with CAR T cells works in leukemias where the antigens are essential for leukemia growth but solid tumors do not have similar antigens essential for cancer growth.

Adoptive therapy with ex vivo expanded immune cells has led to complete responses in solid tumors but the immune responses have been to unanticipated antigens.

Checkpoint inhibitor (CKI) therapy has caused outstanding regressions but only in ~ 25% of all patients but only in patients with evidence that supports the presence of an immune response to cancer: hot cancers defined by tumor infiltrating immune cells, high tumor mutational burden and upregulation of PD-L1 a ligand that stimulates expression of checkpoint inhibitors that block immune responses.

Cold cancers like advanced colorectal carcinoma (CRC) lack these characteristics and only have a 7% response to CKI therapy.

Our hypothesis is that primary active immune responses can be induced in cold solid tumors through induction of Immunogenic Cell Death (ICD), a primordial process that invokes host responses to kill invading organisms like viruses and bacteria, and that such responses can be amplified by CKI therapy, multipeptide vaccines or repeat induction of ICD to reject established tumor.

Immunogenic Cell Death primes strong immune responses in subjects without knowing what antigens may be involved.

Our agnostic method is to sensitize subjects with a mixture of Oxaliplatin and a conditionally replicating chimeric human adenovirus injected into cancers that would otherwise kill the subject.

The mixture of Oxaliplatin-virus injected into tumor causes ICD, a form of pre-apoptotic cell death in which malignant cells are turned inside out causing neoantigens inside the cells to be externalized with chaperones and other signals that attract dendritic cells and support cross-priming to tumor antigens.

Our intended clinical use is in patients with liver metastases from advanced CRC. Oxaliplatin is a FDA- approved cytotoxic agent.

The virus conditionally replicates in human malignant cells but not normal adult human cells or in mouse cells, is oncolytic and acts as an immunogen when mixed with Oxaliplatin.

In our preclinical CT26 rectal carcinoma model in BALB/c mice all 6 mm diameter tumors injected with a single intratumoral mixture of Oxaliplatin and virus undergo a 90% reduction in size, 40% of mice had a complete response with 20% being durable.

The responses are associated with a four-fold increase in tumor-infiltrating lymphocytes, induction of lymphocyte cytotoxicity to tumor as well the ability to reject a viable tumor cell challenge - all without CKI therapy.

In this VA Merit application we propose the following aims to begin to transition agnostic immunization to the clinic to improve the health of US Veterans, their beneficiaries and the general public: Aim 1) Confirm the effector cells involved in the immune response to CT26 and 4T1, Aim 2) Identify the antigens targeted by ICD, Aim 3) Define whether adding either CKI therapy, a multipeptide antigen boost or repeating ICD improves complete responses rates in the CT26 and 4T1 models and in the presence of distant disease, and Aim 4) Establish how virus and Oxaliplatin distribute throughout tumor nodules or metastases by analyzing virus location with the distribution of Platinum (Pt) from the Oxaliplatin by inductively coupled plasma mass spectrometry (ICP- MS).

The long term goal of this project is to transition this agnostic vaccine to the clinic so that it may aid the survival of Veterans who develop advanced colorectal carcinoma that at this time has poor responses to the current generation of immuno-oncology agents.