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

Abstract

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.

Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway

“…75−79 Although the exact explanation for the limited response rate is being researched, the current view is that responsiveness to immune checkpoint inhibitors is dependent on the presence of TILs that express immune checkpoint receptors. 11,80−83 Moreover, there appears to be a requirement for a high burden of nonsynonymous DNA mutations at the cancer site to develop a hot immune microenvironment. 10,11 These mutations give rise to potent neo-epitopes that are presented to T-cells by class I major histocompatibility complex on antigen-presenting dendritic cells.…”

Durable intracranial and extracranial response to nivolumab with appearance of secondary resistance in a heavily pretreated patient with head and neck cancer

“…All of these treatments, including surgery, may have contributed to modifying the immune microenvironment of the tumor, making it more sensitive to immunotherapy. [14][15][16][17][18][19][20] After an initial major response, our patient's tumor slowly progressed in two locations during nivolumab treatment. Although radiological pseudoprogression seems to be infrequent in head and neck cancer, caution should be applied when using 18 F-FDG PET scans for tumor reevaluation in patients receiving immunotherapy, as increases in metabolic uptake can occur due to inflammatory cell infiltration and be confounded with tumor progression.…”

“…Our patient underwent a laryngectomy 6 months prior to receiving cetuximab in combination with paclitaxel and cisplatin. All of these treatments, including surgery, may have contributed to modifying the immune microenvironment of the tumor, making it more sensitive to immunotherapy …”

Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma

“…These mechanisms may amplify the anti-tumour immune response by integrating the activity of T, B, and NK cells through antibody-directed cell cytotoxicity. 36 Due to the high expression of PD1 on Tfh cells, the effects of anti-PD1 therapy on Tfh function may have implications for immunotherapeutic success and warrants further investigation.…”