ASCO 2017: Immune response results from vesigenurtacel-l (HS-410) in combination with BCG from a randomized phase 2 trial in patients with non-muscle invasive bladder cancer (NMIBC)

Chicago, IL (UroToday.com) While the recent emphasis and interest has been focused on the novel therapies for muscle-invasive bladder cancer (MIBC), non-MIBC (NMIBC) still represents 70% of the patients who present with bladder cancer (BC). High-grade NMIBC represents a particularly troublesome cohort for whom clinical progression to MIBC remains a high risk, but for whom there are not many treatment options.

BCG instillations (induction and maintenance) remain the standard of care for this patient population. While alternative treatment regimens, both systemic and intravesical have been explored, none have proven superior to BCG alone without significantly increasing the morbidity of treatment.

While the exact mechanism of BCG is not perfectly defined, we do know that it initiates a local inflammatory response, that in turns simultaneously treats NMIBC. Vesigenurtacel-L (HS-410) is a novel vaccine comprised of an allogeneic cell line, selected for high expression of a series of bladder tumor antigens (neoantigens) and transfected with gp96-Ig. Upon being delivered to a recipient's own antigen presenting cells (APCs), the neoantigens activate CD8+ cytotoxic T cells. In this, they help ramp up the patient’s own BCG-induced immune response to bladder cancer specific targets.

Study Design:
In this two part study, there is a phase 1 (open-label safety study) and a phase 2 efficacy study. In the 1st phase, the patients who had previously received 3-6 instillations of weekly intravesical Bacillus Calmette-Guerin (BCG) induction therapy were subsequenty treated with low dose intradermal (1x106 cells) HS-410 monotherapy. In the 2nd phase, patients scheduled for standard of care BCG treatment are randomized into 3 arms: placebo, low-dose, or high-dose intradermal injections. This is given along with BCG. A 4th arm of just high-dose HS-410 was added.

Ultimately, 94 patients with intermediate- (n = 5) or high-risk (n = 73) NMIBC who were either BCG-naïve or recurrent, with or without carcinoma in situ (CIS), were enrolled 1:1:1:1 to one of two doses of HS-410 (either 106 or 107 cells/dose) with 6 weeks of induction BCG, BCG monotherapy, or high-dose HS-410 monotherapy. This was followed by 6 more weeks of HS-410 in the induction phase. Maintenance treatment consisted of 3-weekly treatments at the following timepoints: 3 mo, 6 mo, and 12 mo. Concurrently, 16 patients (1 int. risk, 15 high-risk) were enrolled in an open-label monotherapy HS-410 arm for patients who did not receive BCG. The primary endpoint was 1-year RFS. Secondary immune evaluations include ELISPOT, tumor IHC, tumor antigen profiling, flow cytometry, urine cytokine analysis, and T cell receptor sequencing.

Results:
The median age was 69-73 across the groups, and they were predominantly male. Except for arm 4, most patients were BCG-naïve (61-69%). 

Tolerability – HS-410 was well tolerated in both phase studies. Adverse event profiles were similar across the treatment arms.

Immune response - IFNγ ELISPOT assay demonstrated a high baseline response to HS-410. Responses to overlapping peptide pools of HS-410 derived antigens defined immune responders (doubling of IFNγ-secreting cells). IHC demonstrated that ~60% of NMIBC patient tumor biopsies were tumor infiltrating lymphocyte (TIL) negative at baseline (n = 84), but that only ~15% of tumor biopsies were TIL negative post treatment (n = 40). TIL IHC analysis may also be able to classify responders vs. non-responders.

Clinical outcomes: Not presented at this time. 

Limitations / Discussion Points:
No clinical outcomes were reported.

While there is a dire need for BCG alternatives or BCG augmenting therapies, further study is warranted.

Presented By: Gary D. Steinberg, MD, Section of Urology, Department of Surgery, University of Chicago Pritzker School of Medicine, Chicago, IL

Co-Author(s): Neal D. Shore, Lawrence Ivan Karsh, James L. Bailen, Trinity Bivalacqua, Karim Chamie, James S. Cochran, Richard David, Robert L. Grubb, Wael A. Harb, Jeffrey M. Holzbeierlein, Ashish M. Kamat, Edouard John Trabulsi, William Vincent Walsh, Michael Brandon Williams, Fredrick Wolk, Michael Woods, Melissa Leigh Price, Brandon Early, Taylor Houghton Schreiber

Institution(s): Carolina Urologic Research Center, Myrtle Beach, SC; The Urology Center of Colorado, Denver, CO; First Urology Research, Louisville, KY; Johns Hopkins Hospital, Baltimore, MD; University of California, Los Angeles, Los Angeles, CA; Urology Clinics of North Texas, Dallas, TX; Skyline Urology, Sherman Oaks, CA; Washington University School of Medicine in St. Louis, St. Louis, MO; Horizon Oncology Center, Lafayette, IN; The University of Kansas Hospital, Kansas City, KS; The University of Texas MD Anderson Cancer Center, Houston, TX; The Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA; University of Massachusetts Medical School, Worcester, MA; MD Anderson Cancer Center, Virginia Beach, VA; Skyline Urology, Torrance, CA; The University of North Carolina at Chapel Hill, Chapel Hill, NC; Heat Biologics, Durham, NC

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA

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