Cancer vaccine: learning lessons from immune checkpoint inhibitors

Ye, Zhenlong; Qian, Qiming; Jin, Haixia; Qian, Qijun

doi:10.7150/jca.20059

Cited by 40 publications

(24 citation statements)

References 75 publications

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“…These terminally differentiated T cells also exhibit negative costimulatory molecules (i.e., CTLA4, PD1, Tim-3) that correlate with T-cell dysfunctionality or exhaustion and have limited life span in vivo, making them less likely to mediate clinical responses (49,50). On the basis of the promising results seen when using checkpoint blockade, it is important that the mechanisms underlying the resistance to these therapies are better understood and targeted for increasing the efficacy of tumor control across various tumor types (51)(52)(53). Thus, strategies that could potentiate antitumor immunotherapy are needed.…”

Section: Discussionmentioning

confidence: 99%

Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response

Chatterjee

Chakraborty

Daenthanasanmak

et al. 2019

Clinical Cancer Research

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Purpose: Adoptive T-cell therapy (ACT) of cancer, which involves the infusion of ex vivo-engineered tumor epitope reactive autologous T cells into the tumor-bearing host, is a potential treatment modality for cancer. However, the durable antitumor response following ACT is hampered either by loss of effector function or survival of the antitumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the antitumor T cells are of immense importance. Given the role of metabolism in determining the therapeutic efficacy of T cells, we hypothesize that inhibition of PIM kinases, a family of serine/threonine kinase that promote cell-cycle transition, cell growth, and regulate mTORC1 activity, can improve the potency of T cells in controlling tumor.Experimental Design: The role of PIM kinases in T cells was studied either by genetic ablation (PIM1 À/À PIM2 À/À PIM3 À/À ) or its pharmacologic inhibition (pan-PIM kinase inhibitor, PimKi). Murine melanoma B16 was established subcutane-ously and treated by transferring tumor epitope gp100-reactive T cells along with treatment regimen that involved inhibiting PIM kinases, anti-PD1 or both.Results: With inhibition of PIM kinases, T cells had significant reduction in their uptake of glucose, and upregulated expression of memory-associated genes that inversely correlate with glycolysis. In addition, the expression of CD38, which negatively regulates the metabolic fitness of the T cells, was also reduced in PimKi-treated cells. Importantly, the efficacy of antitumor T-cell therapy was markedly improved by inhibiting PIM kinases in tumor-bearing mice receiving ACT, and further enhanced by adding anti-PD1 antibody to this combination.Conclusions: This study highlights the potential therapeutic significance of combinatorial strategies where ACT and inhibition of signaling kinase with checkpoint blockade could improve tumor control.

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Section: Discussionmentioning

confidence: 99%

Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response

Chatterjee

Chakraborty

Daenthanasanmak

et al. 2019

Clinical Cancer Research

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“…It appears also relevant in a therapeutic perspective to distinguish between individuals harboring rapidly progressing cancers and those with early stage tumors or premalignancies, since the latter may not benefit from immunotherapy. This is particularly important as trials are being developed that use checkpoint inhibitors like anti-PD1 as a cancer prevention strategy in individuals at high risk [ 59 , 60 ].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Is adaptive therapy natural?

et al. 2018

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Research suggests that progression-free survival can be prolonged by integrating evolutionary principles into clinical cancer treatment protocols. The goal is to prevent or slow the proliferation of resistant malignant cell populations. The logic behind this therapy relies on ecological and evolutionary processes. These same processes would be available to natural selection in decreasing the probability of an organism’s death due to cancer. We propose that organisms’ anticancer adaptions include not only ones for preventing cancer but also ones for directing and retarding the evolution of life-threatening cancer cells. We term this last strategy natural adaptive therapy (NAT). The body’s NAT might include a lower than otherwise possible immune response. A restrained immune response might forego maximum short-term kill rates. Restraint would forestall immune-resistant cancer cells and produce long-term durable control of the cancer population. Here, we define, develop, and explore the possibility of NAT. The discovery of NAT mechanisms could identify new strategies in tumor prevention and treatments. Furthermore, we discuss the potential risks of immunotherapies that force the immune system to ramp up the short-term kill rates of malignant cancer cells in a manner that undermines the body’s NAT and accelerates the evolution of immune resistance.

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“…All such clinical trials are currently recruiting patients and results are expected to be available in the coming months (review in. 102 ) None of such combinatorial strategies have been evaluated in HCC yet, but positive results reported in clinical trials evaluating checkpoint inhibitors in liver cancer 103 strongly suggest that cancer vaccine and checkpoint combinations may show better efficacy also in HCC. Instead, the combination of checkpoint inhibitors with co-stimulatory molecules such as CD137 (4-1BB), CD134 (OX40), glucocorticoid-induced tumor necrosis factor receptor (GITR) or CD40 has been evaluated in a preclinical study using an aggressive transgenic hepatocellular carcinoma mouse model.…”

Section: Enhancing Cancer Vaccine Efficacy In Hcc By Combinatorial Stmentioning

confidence: 99%

Potentiating cancer vaccine efficacy in liver cancer

Tagliamonte¹,

Petrizzo²,

Mauriello³

et al. 2018

OncoImmunology

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Hepatocellular carcinoma (HCC) is the most common liver malignancy with a poor prognosis and an overall 5-year survival rate of approximately 5-6%. This is due because standard of care treatment options are limited and none of them shows a sufficient efficacy. HCC is an "inflammation-induced cancer" and preliminary preclinical and clinical data suggest that immunotherapeutic approaches may be a good alternative candidate for the treatment of HCC patients improving the dismal prognosis associated with this cancer. However, recent findings strongly suggest that an optimal immunotherapy in HCC requires the combination of an immune activator with immune modulators, aiming at compensating the strong liver immune suppressive microenvironment. One of the most promising strategy could be represented by the combination of a cancer vaccine with immunomodulatory drugs, such as chemotherapy and checkpoint inhibitors. Very limited examples of such combinatorial strategies have been evaluated in HCC to date, because HCC easily develops resistance to standard chemotherapy, which is also poorly tolerated by patients with liver cirrhosis. The present review describes the most update knowledge in this field.

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Cancer vaccine: learning lessons from immune checkpoint inhibitors

Cited by 40 publications

References 75 publications

Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response

Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response

Is adaptive therapy natural?

Potentiating cancer vaccine efficacy in liver cancer

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