Immunomodulatory Effects in a Phase II Study of Lenalidomide Combined with Cetuximab in Refractory KRAS-Mutant Metastatic Colorectal Cancer Patients

Gandhi, Anita K.; Shi, Tao; Li, Mingyu; Jungnelius, Ulf; Romano, Andrea; Tabernero, Josep; Siena, Salvatore; Schäfer, Peter; Chopra, Rajesh

doi:10.1371/journal.pone.0080437

Cited by 30 publications

(26 citation statements)

References 18 publications

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“…Indeed, the occurrence of autoimmunity and/or inflammatory disease following a specific immune-treatment appears to be consequent to active and complex immunological phenomena occurring in the tumor microenvironment [35]. These events can cause tissue damage, acute inflammation, antigen release/cross-presentation, which in turn trigger a process of antigen cascade with the final result of a more efficient multi-antigen-specific response [19,22,31,33,36]. Furthermore, the occurrence of autoimmunity following patient immunotherapy revealed to be a strong favorable outcome and prolonged survival predictor in different clinical trials [19,31,33].…”

Section: Discussionmentioning

confidence: 99%

Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients

Cusi

Botta

Pastina

et al. 2015

Cancer Immunol Immunother

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Thymidylate synthase (TS) poly-epitope peptide (TSPP) is a 27-mer peptide vaccine containing the amino acidic sequences of three epitopes with HLA-A2.1-binding motifs of TS, an enzyme overexpressed in cancer cells, which plays a crucial role in DNA repair and replication. Based on the results of preclinical studies, we designed a phase Ib trial (TSPP/VAC1) to investigate, in a dose escalation setting, the safety and the biological activity of TSPP vaccination alone (arm A) or in combination with GM-CSF and IL-2 (arm B) in cancer patients. Twenty-one pretreated metastatic cancer patients, with a good performance status (ECOG ≤ 1) and no severe organ failure or immunological disease, were enrolled in the study (12 in arm A, nine in arm B) between April 2011 and January 2012, with a median follow-up of 28 months. TSPP resulted safe, and its maximal tolerated dose was not achieved. No grade 4 toxicity was observed. The most common adverse events were grade 2 dermatological reactions to the vaccine injection, cough, rhinitis, fever, poly-arthralgia, gastro-enteric symptoms and, to a lesser extent, moderate hypertension and hypothyroidism. We detected a significant rise in auto-antibodies and TS-epitope-specific CTL precursors. Furthermore, TSPP showed antitumor activity in this group of pretreated patients; indeed, we recorded one partial response and seven disease stabilizations (SD) in arm A, and three SD in arm B. Taken together, our findings provide the framework for the evaluation of the TSPP anti-tumor activity in further disease-oriented clinical trials.

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Section: Discussionmentioning

confidence: 99%

Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients

Cusi

Botta

Pastina

et al. 2015

Cancer Immunol Immunother

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“…3,4 Likewise, there has been considerable attention towards the development of small molecule cancer therapeutics that affect immune system targets, although there are still very few currently available agents. 5–8 …”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

Gromek

deMayo

Maxwell

et al. 2016

Bioorganic & Medicinal Chemistry

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Santacruzamate A (SCA) is a natural product isolated from a Panamanian marine cyanobacterium, previously reported to have potent and selective histone deacetylase (HDAC) activity. To optimize the enzymatic and cellular activity, 40 SCA analogues were synthesized in a systematic exploration of the zinc-binding group (ZBG), cap terminus, and linker region. Two cap group analogues inhibited proliferation of MCF-7 breast cancer cells, with analogous increased degranulation of cytotoxic T cells (CTLs), while one cap group analogue reduced CTL degranulation, indicative of suppression of the immune response. Additional testing of these analogues resulted in reevaluation of the previously reported SCA mechanism of action. These analogues and the resulting structure-activity relationships will be of interest for future studies on cell proliferation and immune modulation.

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“…Interestingly, the ability of lenalidomide to stimulate NK cell activity has been reported to be diminished by concurrent dexamethasone treatment [142]. Due to its ability to stimulate cytokine production and enhance ADCC activity, lenalidomide has been studied in combination with cetuximab for colorectal and head and neck cancer [143, 144]. …”

Section: Imids and Monoclonal Antibodiesmentioning

confidence: 99%

Immunomodulatory Drugs in Multiple Myeloma: Mechanisms of Action and Clinical Experience

Holstein

McCarthy

2017

Drugs

180

174

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Over the last two decades, the outcomes for patients with multiple myeloma, a plasma cell malignancy, have dramatically improved. The development of the immunomodulatory drugs (IMiDs) which include thalidomide, lenalidomide, and pomalidomide, has contributed significantly to these improved outcomes. While thalidomide is now less commonly prescribed, lenalidomide is widely used in the treatment of newly diagnosed transplant-eligible and transplant-ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting. The IMiDs have been reported to have a multitude of activities, including anti-angiogenic, cytotoxic, and immunomodulatory, however, the more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3, have provided greater insight into their mechanism of action. Here the clinical efficacy of these agents in myeloma is reviewed as well as discussion of structure-function relationship, the molecular mechanisms of action, and the association of IMiDs with second primary malignancies and thrombosis.

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Immunomodulatory Effects in a Phase II Study of Lenalidomide Combined with Cetuximab in Refractory KRAS-Mutant Metastatic Colorectal Cancer Patients

Cited by 30 publications

References 18 publications

Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients

Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients

Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

Immunomodulatory Drugs in Multiple Myeloma: Mechanisms of Action and Clinical Experience

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