CUA 2018: Factors of Antitumor Responses in the Clinical Setting to Improve the Clinical Benefit of Immunotherapy in GU Malignancies

Halifax, Nova Scotia (UroToday.com) The lecture was directed at covering current understanding of immunological mechanisms responsible for the tumor-host interaction and review the most recent clinical successes in the immunology of bladder and kidney cancers. Finally, to provide a perspective and some examples of the immense potential of combined immunotherapies for genitourinary cancers. 

Yves Fradet, MD, started off his lecture by referencing the work from the Canadian Urologic Oncology Group published in 1998 in New England Journal of Medicine. The study was first in its kind to assess the interferon gamma-1b compared with placebo in metastatic renal cell carcinoma.  Of 197 patients with biopsy-proven metastatic renal cell carcinoma, 3.3% demonstrated a complete response to the treatment, while 1.1% showed partial response1. He continued discussing the extraordinary power of Immune system, a discovery by Canadian scientist, Dr. Alvaro Morales from Queens University in 1976. Authors first reported on the intracavitary use of Bacillus Calmette-Guerin (BCG) in the treatment of superficial bladder tumors2.  These studies followed a successful discovery of BCG in Canada by Douville et al, in 1978 with subsequent FDA approval in 1980.

Since the initial reports and discoveries in immunotherapy of GU cancers, there has been a lot of progress in the field of immune therapy. Fradet stated that with additional discoveries of different strains of BCG, they are outcomes significantly differ. He references a study published in 2015 in European Urology journal from Rentsch and colleagues. They demonstrated that recurrence and progression rates for different types of BCGs are totally different. Authors performed a prospective randomized single institution trial with BCG Connaught or Tice. Recurrence-free survival was significantly higher in patients treated with Connaught strain of BCG3

He further discussed the new era of immune therapy based on check-point inhibition. He gave an analogy of high-speed vehicle with breaks. Nivolumab in phase I and II studies in RCC patients demonstrated significant clinical activity, with response rates of above 30%. This led to the further design of prospective clinical trials, including 821 patients with advanced clear cell RCC. Treatment with nivolumab was better tolerated than everolimus; with median PFS was 4.6 months with nivolumab and 4.4 months with everolimus. Similarly, PD1 inhibition signals serve as check-points in the development of malignancies. In this regard, the new immune checkpoint inhibitors such as Anti-CTLA4, Antezolizumab have been engineered to significantly reduce antibody-dependent cellular cytotoxicity and have demonstrated encouraging results in a phase I monotherapy study in metastatic RCC patients with a response rate of 15% with a duration of 17 months.  Anti-PD1, anti-PD-L1 pathway blockers also work in a similar manner. He also mentioned B7 activators who happened to have a significant role in checkpoint immune system. In comparison to Anti-PD blockers, B7 activators work in a reverse mechanism by activating the inhibitory check-points of the immune system. The combined blockade of PD-1/PDL1 along with CTLA-4 has been shown to further augment responses in patients advanced disease. 

Immunotherapy for Prostate Cancer (PCa):
PCa is curable when diagnosed and treated early. However, when the disease is advanced and there is distant metastasis, the disease will eventually progress to become castration resistant. The rationale behind immunotherapy in PCA is to generate and mount a strong and effective immune response against PCA related antigens, which can potentially lead to destruction and elimination of malignant cells. Dr. Fradet discussed novel genes and drugs including Sipuleucel, which is a cell-based vaccine manufactured from the patient’s own peripheral blood mononuclear cells.

Fradet concluded his lecture that several immune checkpoint agents, used alone or in combination with other chemotherapeutics, vaccines, and monoclonal antibodies, are being tested in clinical settings. Our comprehensive understanding of the underlying factors of antitumor responses in the clinical setting will further improve the clinical benefit of immunotherapy in GU malignancies including prostate, bladder, and kidney. 

References:
1. Gleave, M. E., et al. (1998). "Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group." N Engl J Med 338(18): 1265-1271.
2. Morales, A., et al. (1976). "Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors." J Urol 116(2): 180-183.
3. Rentsch, C. A., et al. (2014). "Bacillus Calmette-Guerin strain differences have an impact on clinical outcome in bladder cancer immunotherapy." Eur Urol 66(4): 677-688.

Presented by: Yves Fradet, MD, CHU de Quebec – Universite Laval – L’Hotel-Dieu de Quebec, Quebec, Canada

Written By: Zhamshid Okhunov, MD Twitter: @OkhunovZham Department of Urology, University of California-Irvine, medical writer for UroToday.com at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia
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