Immune Checkpoint Blockade in Cancer Therapy

Allison, James P.

doi:10.1001/jama.2015.11929

Cited by 76 publications

(45 citation statements)

References 8 publications

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“…Immune checkpoint inhibitor (CPI) therapy such as CTL-associated protein 4/programmed cell death 1 (CTLA4/PD-1) inhibition exhibits considerable antitumor activity in the clinic (20)(21)(22). Because the main mechanism of CTLA4/PD-1 inhibition therapy is antitumor T-cell activation, the success of CPI therapy is largely dependent on T-cell infiltration into the tumor (23,24).…”

Section: Introductionmentioning

confidence: 99%

Improving Efficacy and Safety of Agonistic Anti-CD40 Antibody Through Extracellular Matrix Affinity

Ishihara

Potin

et al. 2018

Molecular Cancer Therapeutics

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CD40 is an immune costimulatory receptor expressed by antigen-presenting cells. Agonistic anti-CD40 antibodies have demonstrated considerable antitumor effects yet can also elicit serious treatment-related adverse events, such as liver toxicity, including in man. We engineered a variant that binds extracellular matrix through a super-affinity peptide derived from placenta growth factor-2 (PlGF-2) to enhance anti-CD40's effects when administered locally. Peritumoral injection of PlGF-2-anti-CD40 antibody showed prolonged tissue retention at the injection site and substantially decreased systemic exposure, resulting in decreased liver toxicity. In four mouse tumor models, PlGF-2-anti-CD40 antibody demonstrated enhanced antitumor efficacy compared with its unmodified form and correlated with activated dendritic cells, B cells, and T cells in the tumor and in the tumor-draining lymph node. Moreover, in a genetically engineered melanoma model that does not respond to checkpoint inhibitors, PlGF-2-anti-CD40 antibody treatment enhanced T-cell infiltration into the tumors and slowed tumor growth. Together, these results demonstrate the marked therapeutic advantages of engineering matrix-binding domains onto agonistic anti-CD40 antibody as a therapeutic given by tumori-regional injection for cancer immunotherapy. Extracellular matrix-binding peptide conjugation to agonistic anti-CD40 antibody enhances antitumor efficacy and reduces treatment-related adverse events. .

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Section: Introductionmentioning

confidence: 99%

Improving Efficacy and Safety of Agonistic Anti-CD40 Antibody Through Extracellular Matrix Affinity

Ishihara

Potin

et al. 2018

Molecular Cancer Therapeutics

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“…Following the success of vaccines against xenogeneic infectious diseases, the tacit assumption was that host immunity would also be protective against isogeneic cancer [3]. Cancer immunotherapy trials, however, conducted with the best available science resulted in anecdotal responses such that the field of cancer immunotherapy did not quite succeed in fulfilling the great hopes of conquering cancer and began to lose credibility [4].…”

Section: Introductionmentioning

confidence: 99%

“…Studies initiated by J. P. Allison led to a clinical breakthrough via the translation of immune checkpoint inhibitors (ICIs) [4] [5]. A recent special issue of Science entitled, The Cancer Immunotherapy Revolution, reviewed the newly approved immunotherapies that can manipulate components of the immune system to attack tumors [6].…”

Section: Introductionmentioning

confidence: 99%

Exploiting Autoimmunity Unleashed by an Off-Label Low-Dose Immune Checkpoint Blockade to Treat Advanced Cancer

Bakács¹,

Moss²,

Szász³

et al. 2018

Preprint

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As a result of the cancer immunotherapy revolution hundreds of clinical trials of the newly approved immunotherapies are now under way to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by blockade of co-inhibitory signals. While success stories of terminal cancer patients achieving complete remissions are accumulating, not enough research has been done into the risks of the new therapies. Since the use of immunotherapy is becoming more common, and is expected to develop into first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the nemesis of immunotherapy. Immune-related adverse events (IrAEs) could affect any tissue, their incidence may reach up to 90% of patients and toxicity is dose-dependent. While the combination of two immune checkpoint inhibitors (ICIs) increased efficacy, the incidence of severe adverse events was also increased. Apparently, ICIs cannot be restricted to the targeted anti-tumor T cell population. The long lasting objective of cancer regression can only be achieved by paying a price: tolerance to healthy self tissues is compromised. In the face of an ipilimumab induced pan-lymphocytic activation, a therapeutic paradigm shift is required. The task is not desperately trying to put the genie back in the bottle by immune suppressive treatments, but instead harnessing the autoimmune forces by an off label low-dose combined anti-CTLA-4 and anti-PD1 antibody blockade, which is supplemented with conventional interleukin-2 stimulation and hyperthermia. The proof-of-principle of the low-dose-combination therapy was demonstrated in a heavily pre-treated triple negative breast cancer (TNBC) patient with far advanced pulmonary metastases and severe shortness of breath, who had exhausted all conventional treatment. Her pulmonary metastases went into complete remission with transient WHO I-II diarrhea and skin rash. She lived for 27 months after starting the low-dose-combination therapy. She had recurrence as a sternal mass and pleural metastases up to 3 cm. Since the low-dose-combination protocol consists only of approved drugs and treatments, this exceptional response should instigate further research efforts.

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“…Monoclonal antibodies (mAbs) targeting the programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) pathway have achieved impressive response rates in patients with melanoma, non-small cell lung cancer, and bladder cancer, and PD-L1 has been validated as a predictive biomarker for the outcome of mAb therapy in many studies 14–16 . However, its prognostic and clinical value in patients with Xp11.2 RCC subtypes is unknown.…”

Section: Introductionmentioning

confidence: 99%

PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness

Chang

Dai

et al. 2017

Sci Rep

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Programmed death ligand-1 (PD-L1), a promising antitumor target, has proven clinical value against many malignancies. However, the PD-L1 content of Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) and its correlation with clinical outcomes remain unclear. This study aimed to investigate PD-L1 expression in Xp11.2 RCC and to assess its prognostic value. Formalin-fixed paraffin-embedded specimens from 36 adult patients that were histologically confirmed (by fluorescence in situ hybridization) were subjected to immunohistochemical analysis. Of the 36 Xp11.2 RCC patients, 9 (25.0%) had tumors with positive PD-L1 expression and 27 (75.0%) had tumors with negative PD-L1 expression. Positive PD-L1 expression correlated with advanced tumor stage (P = 0.001), regional lymph node metastasis (P < 0.001), and distant metastasis (P < 0.001). A multivariate analysis identified positive PD-L1 expression was an independent adverse prognostic factor for both progression free survival (hazard ratio: 3.7, P = 0.018) and overall survival (hazard ratio: 4.5, P = 0.034). The median PFS and OS for the whole cohort were 13.0 months (95% confidence interval [CI], 9.4–16.6 months) and 36.0 months (95% CI, 23.9–48.1 months), respectively. Our findings suggest that positive PD-L1 expression is indicative of worse clinical outcome in Xp11.2 RCC. Further studies are needed to explore the potential efficacy of targeting PD-L1 in Xp11.2 RCC.

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Immune Checkpoint Blockade in Cancer Therapy

Cited by 76 publications

References 8 publications

Improving Efficacy and Safety of Agonistic Anti-CD40 Antibody Through Extracellular Matrix Affinity

Improving Efficacy and Safety of Agonistic Anti-CD40 Antibody Through Extracellular Matrix Affinity

Exploiting Autoimmunity Unleashed by an Off-Label Low-Dose Immune Checkpoint Blockade to Treat Advanced Cancer

PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness

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