Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy.

[D.ap]

Abstract


Combination therapy for the treatment of cancer is becoming increasingly essential as we gain improved understanding of the complexity of cancer progression and the mechanisms by which cancer cells become resistant to single-agent therapy. Recent studies, both clinical and preclinical, have suggested that immunotherapy is a promising approach to the treatment of cancer; however, strategies to improve its clinical efficacy are still needed. A number of recent studies have indicated that antiangiogenic tyrosine kinase inhibitors (TKIs) target multiple components of the tumor microenvironment and are an ideal class of agents for synergizing with cancer immunotherapy. TKIs are well known to modulate tumor endothelial cells, leading to vascular normalization; however, these agents have also been recently shown to decrease tumor compactness and tight junctions, thereby reducing solid tumor pressure and allowing for improved perfusion of collapsed vessels and increased tumor oxygenation. In addition, some TKIs are capable of inducing immunogenic modulation, whereby tumor cells are sensitized to killing by T lymphocytes. Moreover, a number of TKIs have been shown to be involved in immune subset conditioning, increasing the frequency and function of effector immune elements, while decreasing the number and function of immune suppressor cells. The alteration of the immune landscape, direct modification of tumor cells, and improved vascular perfusion leads to improved antitumor efficacy when antiangiogenic TKIs are combined with immunotherapy. Collectively, the data presented in this review support the clinical combination of multi-targeted antiangiogenic TKIs, including but not limited to cabozantinib, sunitinib, and sorafenib, as well as to other antiangiogenic therapies, such as the anti-VEGF antibody bevacizumab, with cancer vaccines for improved treatment of solid tumors.

Keywords: cabozantinib, sunitinib, immunotherapy, combination therapy, immune subset conditioning, immunogenic modulation


Conclusions

The observations reviewed here further demonstrate that TKIs induce direct effects on tumor cells leading to their destruction via apoptotic and immune-mediated mechanisms. These observations also support the conclusions that TKIs, particularly antiangiogenic TKIs, modify the tumor microenvironment in multiple ways, including the alteration of immune cell infiltration (immune subset conditioning) leading to tumor eradication particularly when these therapies are combined with cancer immunotherapy. Unfortunately, it is common for cancer cells to become resistant to targeted therapy, particularly to small molecule inhibitors such as TKIs. It is possible that drug resistance could be avoided or overcome by combining these agents with additional therapies with which synergistic antitumor effects can be observed. In addition, the effectiveness of cancer immunotherapy can be compromised when immune cells cannot penetrate the tumor due to abnormal vasculature [44]. Data obtained using the MC38-CEA tumor model indicate that TKIs synergize with the MVA/rF-CEA/TRICOM cancer vaccine to induce changes in the tumor microenvironment resulting in improved immune cell infiltration and sustained tumor regression. The antiangiogenic TKIs described here synergize with cancer immunotherapy by targeting 3 elements of the tumor microenvironment: (a) tumor endothelial cells, leading to vascular normalization; (b) tumor cells; direct growth inhibition, immunogenic modulation, and reduction of tumor compactness allows collapsed vessels to reopen; and (c) tumor-infiltrating immune cells, increasing the frequency and function of effector immune elements while decreasing the number and function of immune suppressor cells. Collectively, these data support the clinical combination of multitargeted antiangiogenic TKIs, including but not limited to cabozantinib, sunitinib, sorafenib, pazopanib, axitinib, lapatinib, and imatinib, as well as other antiangiogenic therapies such as the anti-VEGF antibody bevacizumab, with cancer vaccines for improved treatment of solid tumors. Additional preclinical studies are warranted to determine the most appropriate schedules for combination therapies that include TKIs.



https://www.ncbi.nlm.nih.gov/m/pubmed/26005708/

[Bonni Hess]

Dear Debbie,
Thank you for sharing this very important information which should be of special interest to everyone in our ASPS Community, and especially those who are currently receiving TKI or Immunotherapy systemic treatment, or both. We have long thought that perhaps Brittany's previous failed GVAX Immunotherapy Vaccine treatment may have in some way positively contributed to her thus far seemingly unique, very successful, sustained, long term response to Cediranib, and we have often posed this theory to her doctors who have told us that could be a possible factor. This is certainly a very exciting time for ASPS research with all of the encouraging progress that is being made.
With deepest gratitude for your dedicated sharing and with special caring thoughts, healing wishes, and continued Hope,
Bonni

[D.ap]

Bonni and Olga and all

What are your feelings on the long term usesge of TKI 's and thier immune suppression tendencies, as we know ASPS can and will raise its indolent head if given the chance .? With immune suppressive chemos

I worry about the conflict of the 2 meds and how possibly a Tki after long time use with immune therapies counter acts and or cancels out the effects of check point inhibitors ? Keeps the immune system from operating 100%?

[D.ap]

Abstract


The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies . Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.






https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458380/