Case sharing | the successful treatment of metastatic kaposi's sarcoma by navullizumab

Kaposi's sarcoma (KS) is an angioproliferative malignancy associated with human herpes virus 8 (HHV-8) and is more common in patients with
human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and chronic immunosuppressive states.

Classic cases of KS without underlying immunosuppression are relatively rare, and typical KS is more often manifested by skin lesions of the lower extremities ^[1,2
].

For patients with advanced KS, chemotherapy drugs are usually used, and most drugs have some effect
.

For patients who do not respond to chemotherapy, especially when they develop resistance to several chemotherapy drugs at the same time, there is currently a lack of optimal therapeutic agents ^[3
].

In some patients, particularly HIV-positive, treatment with immunomodulators such as lenalidomide and bortezomib has some effect, but efficacy still varies ^[4].

Recent studies have reported that immune checkpoint inhibitors (ICIs) can be used as the mainstay of treatment for virus-associated tumors, mainly due to the fact that these tumors contain immunogenic viral neoantigens ^[5].


PD-1 and its ligands are highly expressed in a variety of cancers, mainly through PD-1 mediated effector T cell failure and thus promote immune evasion of tumors^[6
].

Another study reported increased PD-L1 expression in KS-infected monocytes and was associated with an inflammatory environment, suggesting that lytic replication of the virus may induce activation of PD-1 or PD-L1 in KS-associated diseases^[7].


However, there have been few studies on the use of ICIs in the treatment of KS, and the experience has largely come from case reports
.

Here, we report a case of KS patient
who has a complete response to navurizumab.

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Case profile

The patient, male, 82 years old, came to the hospital for erythema and pruritus skin lesions on the back of the thigh, and did not resolve
after 4 weeks of routine treatment.

Pathology on puncture biopsy shows Kaposi sarcoma
.

ELISA tests negative for
HIV.

CT of the abdomen shows multiple lymphadenopathy in the right groin area
.

Patients are followed up regularly after receiving radiotherapy
.

After two years of follow-up and a chest imaging, the results showed a devastative/metastatic lesion
of the T3 vertebrae.

Due to the simultaneous presence of elevated PSA levels, a prostate MRI was performed and showed PI-RADS 5 lesions in
the left peripheral prostate.

Prostate adenocarcinoma
is confirmed by prostate biopsy.

FDG PET-CT shows lesions on the sixth rib, iliac bone, and femur (Figure 1
).

To determine the origin of the lesion and exclude prostate cancer metastases, Ga-68 PET-CT was performed, and imaging showed no significant isotope uptake in PET-CT-labeled lesions (Figure 2).


Thus, lesions on the sixth rib, iliac bone, and femur are considered to be metastases
of Kaposi's sarcoma.

The patient refused interferon therapy
.

After one year, the patient developed persistent anemia, performed upper gastrointestinal endoscopy, and multiple polyp-like lesions with the appearance of ulcerated mucosa were observed in the fundus and gastric body, and pathological results showed Kaposi's sarcoma-gastric metastasis
.

PET-CT shows new parenchymal lesions
in the lungs.

Systemic chemotherapy
was not initiated due to the general poor condition of the patient.

Interferon therapy and alternative immunotherapy options were discussed with the
patient.

The patient asks for immunotherapy
.

Navurizumab is the drug of choice and is started within two weeks at a dose of 3 mg/kg
.

After 12 cycles of immunotherapy administration, neither the FDG-PET assessment nor the upper gastrointestinal endoscopy found lesions
.

Therefore, the patient is thought to have responded to navurizumab and remains in remission at 12 months of follow-up
.

Figure 1 (left) FDG PET-CT image of a patient when diagnosed with prostate cancer

Figure 2 (right) Ga-68 PET-CT image of a patient when he is diagnosed with prostate cancer

discuss

ICIs for the treatment of KS still do not have a definitively uniform efficacy, so it is currently not possible to include it in
the normative treatment guidelines.

Our elucidating of the role of PD-1 in disease progression may provide a new reference
for the treatment of KS and other viral neoantigen-induced tumors.

ICIs for the treatment of KS have entered the clinical trial phase (Table 1
).

Galanina et al.
reported results in 9 patients who received immunotherapy, 51% showed a partial response, 16% showed a complete response, and 33% showed disease stability
.

Three of these cases showed the same gastrointestinal metastases as our case, but no signs
of metastases outside the gastrointestinal tract were observed in these patients.

On the other hand, Salell et al.
observed signs of metastasis of lymph node involvement in a typical case of KS ^[3,8].


Although the efficacy of ICIs in the treatment of KS at this stage is optimistic, the rarity of this disease and the lack of randomized clinical trials make there is still a lack of clinical evidence for ICIs in the treatment of KS
.

Another point is the lack of evidence for the optimal order of administration of systemic treatment of KS
.

For example, interferon therapy induces PD-1 expression in certain malignancies, such as ovarian cancer and melanoma^{, [9-12].}


Before using ICIs in patients with KS, the therapeutic benefits
of drugs such as interferons should be determined.

In summary, ICIs are one
of the effective treatment options for patients with KS.

However, further research is still needed to determine the efficacy of ICIs and the optimal order of their administration in treatment to optimize treatment outcomes
.

Table 1 Ongoing clinical trials of ICIs for the treatment of KS

References

[1] Cesmeci E, Guven DC, Aktas BY, er al.
Case of metastatic kaposi sarcoma successfully treated with anti-PD-1 immunotherapy.
J Oncol Pharm Pract 2021; 27(7):1766-1769.

[2] Stiller CA, Trama A, Brewster DH, et al.
RARECARE Working Group.
Descriptive epidemiology of kaposi sarcoma in Europe.
Report from the RARECARE project.
Cancer Epidemiol 2014; 38:670-678.

[3] Saller J, Walko CM, Millis SZ, et al.
Response to checkpoint inhibitor therapy in advanced classic kaposi sarcoma: a case report and immunogenomic study.
J Natl Compr Canc Netw 2018; 16:797-800.

[4] Pourcher V, Desnoyer A, Assoumou L, et al.
the ANRS 154 Lenakap Trial Group.
Phase II trial of lenalidomide in HIV-infected patients with previously treated kaposi’s sarcoma: results of the ANRS 154 Lenakap trial.
AIDS Res Hum Retroviruses 2017; 33:1-10.

[5] Paydas S, Bagir EK, Deveci MA, et al.
Clinical and prognostic significance of PD-1 and PD-L1 expression in sarcomas.
Med Oncol 2016; 33:93.

[6] Beldi-Ferchiou A, Lambert M, Dogniaux S, et al.
PD-1 mediates functional exhaustion of activated NK cells in patients with kaposi sarcoma.
Oncotarget 2016; 7:72961-72977.

[7] Host KM, Jacobs SR, West JA, et al.
Kaposi’s aarcomaassociated herpesvirus increases PD-L1 and proinflammatory cytokine expression in human monocytes.
mBio 2017; 8:10-12.

[8] Galanina N, Goodman AM, Cohen PR, et al.
Successful treatment of HIV-associated kaposi sarcoma with immune checkpoint blockade.
Cancer Immunol Res 2018; 6:1129-1135.

[9] Abiko K, Matsumura N, Hamanishi J, et al.
IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer.
Br J Cancer 2015; 112:1501-1509.

[10] Kraehnke JB, Grabbe S, Loquai C, et al.
Primary classic kaposi’s sarcoma of lymph nodes in ultrasound resembling lymphatic metastases of a malignant tumor and successful first-line therapy with ipilimumab.
J Clin Investigative Dermatol 2019; 7:5.

[11] Gambichler T and Susok L.
PD-1 blockade for disseminated Kaposi sarcoma in a patient with atopic dermatitis and chronic CD8 lymphopenia.
Immunotherapy 2020; 12:451-457.

[12] Uldrick TS, Goncalves PH, Abdul-Hay M, et al.
Assessment of the Safety of Pembrolizumab in Patients With HIV and Advanced Cancer-A Phase 1 Study.
JAMA Oncol 2019.

Reviewer/Typesetting: Jiang Zhou

Execution: Uni