Successful treatment of advanced alveolar soft part sarcoma with camrelizumab combined with apatinib: a case report

[D.ap]

Successful treatment of advanced alveolar soft part sarcoma with camrelizumab combined with apatinib: a case report


Abstract: Alveolar soft part sarcoma (ASPS) is a rare and highly malignant mesenchymal tumor that primarily affects adolescents and young adults. ASPS is characterized by a slow growth rate, high metastatic potential, and resistance to conventional therapies. The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced malignancies, improving the objective response rate (ORR) and prolonging patient survival. The combination of immunotherapy with targeted therapies can overcome resistance to treatment with ICIs alone. Although substantial progress has been made in various solid tumors, the clinical relevance of ICIs, used alone or in combination with other therapies, in patients with ASPS remains unclear. This is a case report of a 32-year-old man who was diagnosed with advanced ASPS. After 8 months of anlotinib treatment, the patient’s disease progressed and new cerebellar metastases were detected. Radiotherapy was administered in addition to camrelizumab combined with apatinib to treat the brain metastases. The patient achieved partial remission (46%) after 3 months of treatment and did not present any severe side effects. This is the first reported case of the successful treatment of advanced ASPS with camrelizumab combined with apatinib. This case supports the use of a novel treatment regimen for patients with inoperable ASPS or ASPS that is resistant to conventional therapies.

Keywords: Alveolar soft part sarcoma (ASPS); immunotherapy; camrelizumab

Submitted Oct 12, 2020. Accepted for publication Jan 21, 2021.

doi: 10.21037/apm-20-2275




https://apm.amegroups.com/article/view/61583/html

[Olga]

It is a very interesting report.
Two comments:
1. We had numerous cases of the successful brain mets treatment with the radiosurgery or even radiation therapy when performed on a small mets size.
2. ICI alone are often successful in ASPS and it is totally unclear from this case if combination of immunotherapy with TKI was of any benefit versus ICI alone.

[D.ap]

Hi Olga,
I’m wondering that if a met is over a certain size ,if the TKI aids in say the ICIs delivery being more efficiently delivered , rather than leaking into surrounding tissues because of the deregulated vessels at hand .

Vascular permeability and drug delivery in cancers

The endothelial barrier strictly maintains vascular and tissue homeostasis, and therefore modulates many physiological processes such as angiogenesis, immune responses, and dynamic exchanges throughout organs. Consequently, alteration of this finely tuned function may have devastating consequences for the organism. This is particularly obvious in cancers, where a disorganized and leaky blood vessel network irrigates solid tumors. In this context, vascular permeability drives tumor-induced angiogenesis, blood flow disturbances, inflammatory cell infiltration, and tumor cell extravasation. This can directly restrain the efficacy of conventional therapies by limiting intravenous drug delivery. Indeed, for more effective anti-angiogenic therapies, it is now accepted that not only should excessive angiogenesis be alleviated, but also that the tumor vasculature needs to be normalized. Recovery of normal state vasculature requires diminishing hyperpermeability, increasing pericyte coverage, and restoring the basement membrane, to subsequently reduce hypoxia, and interstitial fluid pressure. In this review, we will introduce how vascular permeability accompanies tumor progression and, as a collateral damage, impacts on efficient drug delivery. The molecular mechanisms involved in tumor-driven vascular permeability will next be detailed, with a particular focus on the main factors produced by tumor cells, especially the emblematic vascular endothelial growth factor. Finally, new perspectives in cancer therapy will be presented, centered on the use of anti-permeability factors and normalization agents.

https://www.frontiersin.org/articles/10 ... 00211/full

[D.ap]

Hi Olga,
I’m wondering that if a met is over a certain size ,if the TKI aids in say the ICIs delivery being more efficiently delivered , rather than leaking into surrounding tissues because of the deregulated vessels at hand .

Vascular permeability and drug delivery in cancers

The endothelial barrier strictly maintains vascular and tissue homeostasis, and therefore modulates many physiological processes such as angiogenesis, immune responses, and dynamic exchanges throughout organs. Consequently, alteration of this finely tuned function may have devastating consequences for the organism. This is particularly obvious in cancers, where a disorganized and leaky blood vessel network irrigates solid tumors. In this context, vascular permeability drives tumor-induced angiogenesis, blood flow disturbances, inflammatory cell infiltration, and tumor cell extravasation. This can directly restrain the efficacy of conventional therapies by limiting intravenous drug delivery. Indeed, for more effective anti-angiogenic therapies, it is now accepted that not only should excessive angiogenesis be alleviated, but also that the tumor vasculature needs to be normalized. Recovery of normal state vasculature requires diminishing hyperpermeability, increasing pericyte coverage, and restoring the basement membrane, to subsequently reduce hypoxia, and interstitial fluid pressure. In this review, we will introduce how vascular permeability accompanies tumor progression and, as a collateral damage, impacts on efficient drug delivery. The molecular mechanisms involved in tumor-driven vascular permeability will next be detailed, with a particular focus on the main factors produced by tumor cells, especially the emblematic vascular endothelial growth factor. Finally, new perspectives in cancer therapy will be presented, centered on the use of anti-permeability factors and normalization agents.

https://www.frontiersin.org/articles/10 ... 00211/full

However with every Med comes the side affects/ rebound heart issues etc of TKIs.

The conclusive paragraph-

“ Vascular normalization represents a novel way to use antiangiogenic therapies at lower dosages, simultaneously reducing side effects and improving the efficacy of adjuvant therapies. Because of the relatively small opportunity window and the need for careful dosage regulation to balance normalization and inhibition, this approach is difficult to translate to the clinic – but its potential in cancer and a variety of other medical conditions warrants further study. With the development of a more effective biomarker and a standard experimental procedure, we may be able to move vascular normalization from the bench to our patients’ bedsides.”

https://thepathologist.com/subspecialti ... n/amp.html

[D.ap]

Hi Olga,
I’m wondering that if a met is over a certain size ,if the TKI aids in say the ICIs delivery being more efficiently delivered , rather than leaking into surrounding tissues because of the deregulated vessels at hand .

Vascular permeability and drug delivery in cancers

The endothelial barrier strictly maintains vascular and tissue homeostasis, and therefore modulates many physiological processes such as angiogenesis, immune responses, and dynamic exchanges throughout organs. Consequently, alteration of this finely tuned function may have devastating consequences for the organism. This is particularly obvious in cancers, where a disorganized and leaky blood vessel network irrigates solid tumors. In this context, vascular permeability drives tumor-induced angiogenesis, blood flow disturbances, inflammatory cell infiltration, and tumor cell extravasation. This can directly restrain the efficacy of conventional therapies by limiting intravenous drug delivery. Indeed, for more effective anti-angiogenic therapies, it is now accepted that not only should excessive angiogenesis be alleviated, but also that the tumor vasculature needs to be normalized. Recovery of normal state vasculature requires diminishing hyperpermeability, increasing pericyte coverage, and restoring the basement membrane, to subsequently reduce hypoxia, and interstitial fluid pressure. In this review, we will introduce how vascular permeability accompanies tumor progression and, as a collateral damage, impacts on efficient drug delivery. The molecular mechanisms involved in tumor-driven vascular permeability will next be detailed, with a particular focus on the main factors produced by tumor cells, especially the emblematic vascular endothelial growth factor. Finally, new perspectives in cancer therapy will be presented, centered on the use of anti-permeability factors and normalization agents.

https://www.frontiersin.org/articles/10 ... 00211/full

Olga
Another reason large Mets don’t respond to chemo / and or meds in general..

But most human solid tumors grow with Gompertzian kinetics in which the growth slows and begins to plateau with a decreasing growth fraction as tumor size increases, so that large tumors become relatively insensitive to chemotherapy because of unfavorable cytokinetics.

https://sites.pitt.edu/~super1/lecture/lec0701/l24.htm

A light read😏


“Resistance. Drug resistance is likely the single most important obstacle to getting higher cure rates with chemotherapy. Resistance can be de novo when tumor cells are resistant to drugs from the start, unfortunately a phenomenon shown by many of the most common solid tumors. In acquired drug resistance the tumors are initially responsive, but become resistant with continued treatment. This phenomenon accounts significantly for the fact that only a small percentage of the many tumors that are responsive to chemotherapy can be cured with drugs alone.

By analogy with studies in bacterial populations, tumors consist of a heterogeneous population of cells because of spontaneous mutations from inherent genomic instability. Some of these mutations give rise to a drug-resistant phenotype by chance. Chemotherapy will kill the most sensitive cells and leave the resistant clones to grow out. Clinically it appears that the patient has responded to treatment with a complete or partial remission, but relapse and progression occur later with a form of tumors that is refractory to drugs. Thus small tumors are the most responsive to chemotherapy before multiple resistant subclones have evolved. Indeed regimens that will not work for bulky tumors can be curative in the adjuvant setting. Effective regimens use combination chemotherapy with non-cross-resistant drugs, since the probability that a malignant cell will undergo two simultaneous mutations resulting in resistance to two different classes of drugs is low. Thus the larger the number of non-cross-resistant drugs given at full dose in the regimen, the more likely the treatment will eliminate the entire tumor cell population. There are limitations to these principles. Some agents like the anthracyclines, epipodophyllotoxins ands the alkylating agents are mutagenic and promote the appearance of drug-resistant clones. Also resistance to some agents can result in cross-resistance to others that are distinct mechanistically and structurally. This phenomenon of multiple drug resistance seen with the anthracyclines, vinca alkaloids, epipodophyllotoxins and taxanes, involves a common mechanism with overexpression of either P-glycoprotein (a 170kDa membrane glycoprotein) or of MRP (the multidrug resistance protein - a 190 kDa membrane protein)., both of which are members of the family of ATP-binding cassette proteins. In adult acute myeloid leukemia and neuroblastoma in children the presence of P-glycoprotein at disease presentation gives a worse prognosis. There are modulating agents that block the efflux of drugs caused by P-glycoprotein. Verapamil, quinine and cyclosporine are too toxic at the required doses, but nwer analogues like dexverapamil and the cyclosporine derivative PSC 833 are in clinical trials.

Resistance to anthracyclines and to epipodophyllotoxins can also be due to altered activity or expression of topoisomerase II. Resistance to nitrogen mustard derivatives, nitrosoureas and anthracyclines can also be associated with an enhanced reducing environment from increased detoxification of glutathione with elevated cellular pools of reduced glutathione. Buthione sulfoximine depletes cellular levels of glutathione, and is in clinical trials as a chemosensitizing agent. Failure to undergo apoptosis can also contribute to resistance to both chemo- and radiotherapy. The Bcl-2, BclX and Bax proteins are all involved in the regulation of apoptosis, and may be responsible.”

[Olga]

It is interesting about the large tumors, but it might be not the case in ASPS. In ASPS we often see a very slow growth in the small tumors, and they are very low metabolically do not light on the PET scan. Perhaps an insufficient blood supply when on the size less than 2-5 mm. The growth speed seems to increase when the blood supply is developed. As it was seen from our patient's cases. And yes, TKI are the double edge swords. They limit formation of the new small blood vessels but do not damage the large ones, in absence of the physical space limitations the large ones became normalized, wider. Providing a window of opportunity to deliver the chemotherapy or the immunotherapy into the tumor. Usually there are areas of necrosis/dead end small blood vessels that do not allow some areas of tumor to get killed, when not accessible. Perhaps there are other synergy that might be beneficial in other aspects.