Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation

Immunoglobulin (Ig) G1 antibodies stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab, an IgG1 isotype monoclonal antibody, is a standard-of-care treatment for locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and metastatic colorectal cancer (CRC). Here we review evidence regarding the clinical relevance of cetuximab-mediated ADCC and other immune functions and provide a biological rationale concerning why this property positions cetuximab as an ideal partner for immune checkpoint inhibitors (ICIs) and other emerging immunotherapies. We performed a nonsystematic review of available preclinical and clinical data involving cetuximab-mediated immune activity and combination approaches of cetuximab with other immunotherapies, including ICIs, in SCCHN and CRC. Indeed, cetuximab mediates ADCC activity in the intratumoral space and primes adaptive and innate cellular immunity. However, counterregulatory mechanisms may lead to immunosuppressive feedback loops. Accordingly, there is a strong rationale for combining ICIs with cetuximab for the treatment of advanced tumors, as targeting CTLA-4, PD-1, and PD-L1 can ostensibly overcome these immunosuppressive counter-mechanisms in the tumor microenvironment. Moreover, combining ICIs (or other immunotherapies) with cetuximab is a promising strategy for boosting immune response and enhancing response rates and durability of response. Cetuximab immune activity—including, but not limited to, ADCC—provides a strong rationale for its combination with ICIs or other immunotherapies to synergistically and fully mobilize the adaptive and innate immunity against tumor cells. Ongoing prospective studies will evaluate the clinical effect of these combination regimens and their immune effect in CRC and SCCHN and in other indications

To hyperfractionate or not to hyperfractionate-Is it really a question?

Despite technical advances the last decade, patients with HPV/p16 negative head and neck cancer (being smokers and having affected performance and co-morbidities), still have a poor outcome after treatment. Hyperfractionated radiotherapy with concurrent cisplatin might be a reasonable way to pursue for improving their outcome. This strategy requires that adequate supportive care is available

NK Cells in Immunotherapy: How Important Are They?

AbstractNK cells are able to perform multiple functions, ranging from immunosurveillance to elimination of mutated or damaged cells, through many different cytotoxic mechanisms. Their functions can be very useful for cancer immunotherapy. But to achieve the maximum support from these extraordinary cells it is necessary to know their effector mechanisms and the mechanisms that lead to their suppression. We have briefly summarized some interesting aspect of their role in immunosurveillance of cancer and metastases, the major mechanisms of cell cytotoxicity, in particular their role in antigen dependent cell cytotoxicity, and many promising strategies currently under study to improve the anticancer function of these cells.Finally, we have taken a closer look at cell therapy in this context, comparing CAR-NK cells and CAR-T cells showing the potential advantages of the former over the latter

Follow-up in Head and Neck Cancer: Do More Does It Mean Do Better? A Systematic Review and Our Proposal Based on Our Experience

As the patients population ages, cancer screening increases, and cancer treatments improve, millions more head and neck carcinoma (HNC) patients will be classified as cancer survivors in the future. Change in epidemiology with human papillomavirus related HNC leads to a number of young treated patients. After treatment for HNC intensive surveillance, including ear, nose and throat (ENT) endoscopy, imaging, and serology, confers a survival benefit that became less evident in unresectable recurrence. We performed a comprehensive revision of literature and analyzed the experience of our centre. We revised publications on this topic and added data derived from the interdisciplinary work of experts within medical oncology, ENT, and radiation oncology scientific societies. We retrospectively collected local and distant recurrence of chemoradiation treated patients at Santa Croce and Carle University Hospital. A HNC follow-up program is not already codified and worldwide accepted. There is a need of scheduled follow-up. We suggest adopting a standardized follow-up guideline, although a multidisciplinary approach is frequently requested to tailor surveillance program and treatment on each patient

Genetic and epigenetic factors affect RET gene expression in breast cancer cell lines and influence survival in patients

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The Renin Angiotensin System (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin–angiotensin system (RAS) is a major physiological regulatory pathway controlling salt–water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma