Antibody-dependent cell-mediated cytotoxicity induced by active immunotherapy based on racotumomab in non-small cell lung cancer patients

Segatori, Valeria Inés; Cuello, Héctor; Gulino, Cynthia A.; Malovini, Alberto; Venier, Cecilia; Guthmann, Marcelo D.; Demarco, Ignacio A.; Alonso, Daniel F.; Gabri, Mariano Rolando

doi:10.1007/s00262-018-2188-y

Cited by 22 publications

(7 citation statements)

References 55 publications

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“…The best clinically active heat shock protein for advanced NSCLC patients ACTS as an intracellular chaperone, binding and presenting tumor antigens on specialized APC via MHCI and II molecules, leading to activation of anti-tumor T cells. Racotumomab has been shown to be a maintenance therapy for advanced non-small cell lung cancer (26). The tumor antigen of the CryoVax vaccine comes from a chaperone released by substances inside the tumor.…”

Section: New Approaches To Tumor Immunity Cancer Vaccinesmentioning

confidence: 99%

The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

Zhu

2021

Front. Immunol.

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Cancer immunotherapy is a kind of therapy that can control and eliminate tumors by restarting and maintaining the tumor-immune cycle and restoring the body’s normal anti-tumor immune response. Although immunotherapy has great potential, it is currently only applicable to patients with certain types of tumors, such as melanoma, lung cancer, and cancer with high mutation load and microsatellite instability, and even in these types of tumors, immunotherapy is not effective for all patients. In order to enhance the effectiveness of tumor immunotherapy, this article reviews the research progress of tumor microenvironment immunotherapy, and studies the mechanism of stimulating and mobilizing immune system to enhance anti-tumor immunity. In this review, we focused on immunotherapy against tumor microenvironment (TME) and discussed the important research progress. TME is the environment for the survival and development of tumor cells, which is composed of cell components and non-cell components; immunotherapy for TME by stimulating or mobilizing the immune system of the body, enhancing the anti-tumor immunity. The checkpoint inhibitors can effectively block the inhibitory immunoregulation, indirectly strengthen the anti-tumor immune response and improve the effect of immunotherapy. We also found the checkpoint inhibitors have brought great changes to the treatment model of advanced tumors, but the clinical treatment results show great individual differences. Based on the close attention to the future development trend of immunotherapy, this study summarized the latest progress of immunotherapy and pointed out a new direction. To study the mechanism of stimulating and mobilizing the immune system to enhance anti-tumor immunity can provide new opportunities for cancer treatment, expand the clinical application scope and effective population of cancer immunotherapy, and improve the survival rate of cancer patients.

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Section: New Approaches To Tumor Immunity Cancer Vaccinesmentioning

confidence: 99%

The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

Zhu

2021

Front. Immunol.

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“…The vaccine was well-tolerated with toxicities primarily consisting of grade 1–2 injection site reactions, with no grade 3 events ( 41 ). However, further development of 1E10 (now called racotumomab) was directed in NSCLC rather than SCLC ( 42 ), and has not been pursued further.…”

Section: Immunotherapy Approaches Prior To Checkpoint Inhibitionmentioning

confidence: 99%

Update on the Biology, Management, and Treatment of Small Cell Lung Cancer (SCLC)

2020

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Small-cell lung cancer (SCLC) accounts for 13-15% of all new lung cancer cases in the US. The tumor has a tendency to disseminate early resulting in 80-85% of patients being diagnosed with extensive disease (ES-SCLC). Chemotherapy has provided SCLC patients considerable survival benefits over the past three decades. Nonetheless, most patients relapse and rarely survive beyond 2 years. Despite consistent overall response rates of ≥50%, until recently, median survival times and 2-year survivals only ranged between 7-10 months and 10-20%, respectively. Several chemotherapy agents possess activity against SCLC, both, as single agents and in combinations but etoposide-platinum emerged as the preferred first line regimen. Upon relapse, many patients remain candidates for additional therapy. However, the sensitivity of relapsed SCLC to further therapies is markedly reduced and dependent upon the level and duration of response to the initial treatment (platinum-sensitive vs. resistant relapse). Multiple factors suggest a therapeutic role for immunotherapy in SCLC: (1) SCLC has been associated with immune-mediated paraneoplastic processes (cerebellar degeneration, limbic encephalitis, and Lambert-Eaton syndrome) and patients presenting with these paraneoplastic syndromes have shown more favorable outcomes, suggesting an underlying immune response mechanism. (2) Comprehensive genomic profiling of SCLC indicates that the majority lack functional p53 (90%) and Rb1 (65%). These universal genetic aberrations facilitate poor genomic stability, thus perpetuating the generation of tumor associated antigens, amenable to targeting with immunotherapy. (3) SCLC has one of the highest mutational loads, likely a reflection of the myriad of insults inflicted by smoking-related carcinogens. The relationship between tumor mutational load and response to immune checkpoint inhibitors has been established in multiple solid tumors, including preliminary results in relapsed SCLC. In this manuscript, we review the early (some failed and discontinued, some partly successful, and still ongoing) attempts to incorporate immunotherapy (particularly vaccine based approaches) to the treatment of SCLC, and the latest attempts Saltos et al. Biology, Management and Treatment of SCLC (mostly incorporating the use of checkpoint inhibitors), including those with favorable but preliminary results (CheckMate 032, Keynote 028 and 158), and those with more definitive positive (iMpower 133 and CASPIAN) and negative (CheckMate 331 and 451) results.

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“…A mouse-monoclonal antibody directed against (Neu5Gc)GM3, 14F7 was isolated (129) and further, has been humanized (175). 1E10, the corresponding anti-idiotype to 14F7, named racotumomab has also been tried in humans (176) and also shown to have non-apoptototic cytoxic effects in vitro (177). This antibody is able to bind to multiple malignant tissues including skin cancers, neuroectodermal tumors, genitourinary cancer, non-small cell lung cancer, and gastrointestinal tumors (178–182) and multiple human trials have also been conducted (e.g., NCT01598454, NCT01460472, NCT02998983, NCT01240447).…”

Section: Clinical Application Of Anti-neu5gc Glycan Antibodiesmentioning

confidence: 99%

From “Serum Sickness” to “Xenosialitis”: Past, Present, and Future Significance of the Non-human Sialic Acid Neu5Gc

2019

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The description of “serum sickness” more than a century ago in humans transfused with animal sera eventually led to identification of a class of human antibodies directed against glycans terminating in the common mammalian sialic acid N- Glycolylneuraminic acid (Neu5Gc), hereafter called “Neu5Gc-glycans.” The detection of such glycans in malignant and fetal human tissues initially raised the possibility that it was an oncofetal antigen. However, “serum sickness” antibodies were also noted in various human disease states. These findings spurred further research on Neu5Gc, and the discovery that it is not synthesized in the human body due to a human-lineage specific genetic mutation in the enzyme CMAH . However, with more sensitive techniques Neu5Gc-glycans were detected in smaller quantities on certain human cell types, particularly epithelia and endothelia. The likely explanation is metabolic incorporation of Neu5Gc from dietary sources, especially red meat of mammalian origin. This incorporated Neu5Gc on glycans appears to be the first example of a “xeno-autoantigen,” against which varying levels of “xeno-autoantibodies” are present in all humans. The resulting chronic inflammation or “xenosialitis” may have important implications in human health and disease, especially in conditions known to be aggravated by consumption of red meat. In this review, we will cover the early history of the discovery of “serum sickness” antibodies, the subsequent recognition that they were partly directed against Neu5Gc-glycans, the discovery of the genetic defect eliminating Neu5Gc production in humans, and the later recognition that this was not an oncofetal antigen but the first example of a “xeno-autoantigen.” Further, we will present comments about implications for disease risks associated with red meat consumption such as cancer and atherosclerosis. We will also mention the potential utility of these anti-Neu5Gc-glycan antibodies in cancer immunotherapy and provide some suggestions and perspectives for the future. Other reviews in this special issue cover many other aspects of this unusual pathological process, for which there appears to be no other described precedent.

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Antibody-dependent cell-mediated cytotoxicity induced by active immunotherapy based on racotumomab in non-small cell lung cancer patients

Cited by 22 publications

References 55 publications

The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

Update on the Biology, Management, and Treatment of Small Cell Lung Cancer (SCLC)

From “Serum Sickness” to “Xenosialitis”: Past, Present, and Future Significance of the Non-human Sialic Acid Neu5Gc

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