Dataset Information

Immunogenomic Analysis of Exceptional Responder to ALT-803 (IL-15 Analogue) in BCG Unresponsive Nonmuscle Invasive Bladder Cancer: A Case Series and Review of the Literature.

ABSTRACT: The clinical validity and utility of complex biomarkers have not been extensively studied in bladder cancer. Three patients with nonmuscle invasive bladder cancer [1 patient with an exceptional response; complete response (CR) for 30 months] who failed intravesical BCG were evaluated using an NYS CLEP approved assay, Immune Report Card, which measures programmed death-ligand 1 expression, CD8 T-cell infiltration pattern, mutational burden, and gene expression of 51 immune-related transcripts using RNA-Seq. Patients were tested before being treated under our expanded access protocol for intravesical BCG with ALT-803. Subject 1 had failed his fourth line of therapy, subject 2 had failed only his first line of therapy, and subject 3 had failed his seventh line of therapy. Surprisingly, subject 1 had an unusually prolonged CR which lasted 30 months; subject 2 had the persistent and recurrent disease until 12 months when he then developed a CR; subject 3 had disease recurrence at 3 months, along with progression noted at 6 months. Immunomutational status was extensively evaluated to identify potential alterations that might play a role as predictive markers for subject 1, who had an exceptional response. Compared with subject 3, tumor in subject 1 demonstrated a high level of expression for CTLA4 (immunosuppression) and CD39 (immunosuppressive). Together, an immunosuppressive tumor environment in nonmuscle invasive bladder cancer that have failed prior BCG may respond better to interleukin-15 immunotherapy compared with tumors without an immunosuppressive environment.

SUBMITTER: Huang J

PROVIDER: S-EPMC6783344 | biostudies-literature | 2019 Nov/Dec

REPOSITORIES: biostudies-literature

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Publications

Immunogenomic Analysis of Exceptional Responder to ALT-803 (IL-15 Analogue) in BCG Unresponsive Nonmuscle Invasive Bladder Cancer: A Case Series and Review of the Literature.

Huang Jeffrey J Shiao Stephen L SL Furuya Hideki H Rosser Charles J CJ

Journal of immunotherapy (Hagerstown, Md. : 1997) 20191101 9

The clinical validity and utility of complex biomarkers have not been extensively studied in bladder cancer. Three patients with nonmuscle invasive bladder cancer [1 patient with an exceptional response; complete response (CR) for 30 months] who failed intravesical BCG were evaluated using an NYS CLEP approved assay, Immune Report Card, which measures programmed death-ligand 1 expression, CD8 T-cell infiltration pattern, mutational burden, and gene expression of 51 immune-related transcripts usi ...[more]

PMID: 31107371

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Project description:BackgroundWe set out to determine if the administration of subcutaneous (SQ) ALT-803 was non-inferior to standard intravesical BCG treatment in a carcinogen induced mouse (C57BL/6J) bladder cancer model.MethodsUsing this well-established carcinogen induced mouse model, we studied the effects of various dosing schemas of ALT-803 (SQ alone, SQ with intravesical BCG, intravesical alone, intravesical with intravesical BCG) compared to intravesical BCG alone (positive control) and PBS (negative control). The non-inferiority margin for the difference in bladder weight, as a surrogate for tumor mass, was defined as 7%.ResultsAll treatment groups (i.e., ALT-803 SQ alone, ALT-803 SQ with intravesical BCG, ALT-803 intravesical alone, ALT-803 intravesical with intravesical BCG and intravesical BCG alone) demonstrated a significant reduction in tumor burden as evident by bladder weights and H&E stain (p?<?0.005). Non-inferiority tests between the intravesical BCG alone group and the additional treatment groups showed that SQ ALT-803 alone (p?=?0.04) and BCG plus SQ ALT-803 (p?=?0.009) were non-inferior to intravesical BCG alone. In this model, we did not see an appreciable infiltration of CD4+ T, CD8+ T or CD161/KLRB1+ natural killer (NK) cells in the bladder/tumor. When assessing peripheral blood mononuclear cells, SQ ALT-803 alone resulted in a robust induction of CD8+ T cells (p?<?0.01), NKG2D+ NK cells (p?<?0.005) and CD3+/NKG2D+ NKT cells (p?<?0.005) compared to other groups, while in splenic tissue, SQ ALT-803 alone resulted in a robust induction of CD3+/NKG2D+ NKT cells (p?<?0.005) compared to other groups.ConclusionSubcutaneous ALT-803 treatment alone or in combination with intravesical BCG was well tolerated and was not inferior to intravesical BCG alone. CD8+ T, NKG2D+ NK and CD3+/NKG2D+ NKT cell induction along with induction of key cytokines remain steadfast mechanisms behind ALT-803. The enhanced therapeutic index seen with BCG and ALT-803, administered SQ or intravesically, provides a powerful justification for the further development of these regimens.

Dataset Information

Immunogenomic Analysis of Exceptional Responder to ALT-803 (IL-15 Analogue) in BCG Unresponsive Nonmuscle Invasive Bladder Cancer: A Case Series and Review of the Literature.

Publications

Immunogenomic Analysis of Exceptional Responder to ALT-803 (IL-15 Analogue) in BCG Unresponsive Nonmuscle Invasive Bladder Cancer: A Case Series and Review of the Literature.

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