Autologous tumor cell vaccines for post-operative active-specific immunotherapy of colorectal carcinoma: long-term patient survival and mechanism of function

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Surgery remains the primary curative treatment but nearly 50% of patients relapse as consequence of micrometastatic or minimal residual disease (MRD) at the time of surgery. Spontaneous T-cell-mediated immune responses to CRC tumor-associated antigens (TAAs) in tumor-draining lymph nodes and in the bone marrow (BM) lead to infiltration of the tumors by lymphocytes. Certain types of such tumor-infiltrating lymphocytes (TILs) have a positive and others a negative impact on the patients' prognosis. This review focuses on advances in CRC active-specific immunotherapy (ASI), in particular on results from randomized controlled clinical studies employing therapeutic autologous tumor cell vaccines. The observed improvement of long-term survival is explained by activation and mobilization of a pre-existing repertoire of tumor-reactive memory T cells which, according to recent discoveries, reside in distinct niches of patients' bone marrow in neighborhood with hematopoietic (HSC) and mesenchymal (MSC) stem cells. Interestingly, memory T cells also contain a subset of stem memory T cells (SMTs) in addition to effector (EMTs) and central memory T cells (CMTs). The mechanism of function of a therapeutic vaccine in a chronic disease is distinct from that of prophylactic vaccines which have to generate de novo protective immune responses. The advantage of autologous vaccines for mobilization of a broad and highly individual repertoire of memory T cells will be discussed.

Keywords::

• active-specific immunotherapy
• bone marrow
• cancer stem cell
• dendritic cell
• memory stem cell
• memory T cell
• minimal residual disease
• Newcastle disease virus
• oncolysis
• overall survival
• tumor-associated antigens

Key issues

• Randomized controlled studies employing autologous tumor cell vaccines have shown benefits for colon cancer patients in term of overall survival.

• ATV-NDV appears better than the vaccine ATC/BCG since it improved survival in patients of stage II, III but also IV with operated liver metastasis.

• Main reasons for that and lessons for tumor vaccination are the following:

  • – Vaccination should be performed as early as possible in patients with a competent immune system and minimal tumor load.

  • – Mutation-derived unique tumor antigens dominate as true tumor rejection antigens.

  • – The use of a broad repertoire of unique tumor antigens (expressed by the autologous tumor cell vaccines) allows to activate and recruit tumor-specific memory T cells from the bone marrow of cancer patients.

  • – The tumor antigens of the vaccine should match the memory T-cell repertoire in order to restimulate tumor-specific memory T cells which can be found in the bone marrow.

  • – The use of strong adjuvants (bacteria, viruses) induces the activation of pattern-recognition receptors from the innate immune system with the aim to break immunological tolerance.

• The proposed mechanism for the effectiveness of the ATV-NDV vaccine in terms of survival benefit for cancer patients treated with this vaccine is that this vaccine allows to maintain long-term cancer-reactive memory.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Notes