A Conversation With Arie Belldegrun, MD, FACS, and Allan Pantuck, MD, MS, FACS


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Arie Belldegrun, MD, FACS

Allan Pantuck MD, MS, FACS

The next decade will witness a new renaissance in the use of immunotherapy of renal cell carcinoma. This will be based on combinations of nonspecific immunotherapies, targeted immunotherapies utilizing engineered T cells, augmentation of the anticancer immune response, and likely even combinatory approaches simultaneously using standard molecularly targeted approaches.

—Arie Belldegrun, MD, FACS, and Allan Pantuck, MD, MS, FACS

Cancer Immunotherapy

What is the role of immunotherapy in the treatment of metastatic renal cell carcinoma?

The harnessing of the immune system as an effective treatment for cancer was recently selected by the journal Science as the top scientific Breakthrough of the Year for 2013.1 With this declaration, we are entering into a new era of enthusiasm about the use of immunotherapy in the treatment of cancer, and this shift will undoubtedly have a significant impact on the treatment of advanced renal cell carcinoma as much as any other cancer type over the next decade.

Historically, metastatic renal cell carcinoma did not fit the standard oncologic paradigm and proved to be largely resistant to the usual treatment regimens employed in combating other types of cancer. Trials of cytotoxic chemotherapy, radiation therapy, and hormonal therapy all failed to demonstrate any appreciable effects on survival. Instead, in the 1980s and 1990s, renal cell carcinoma, along with melanoma, became the model for the development of immune-based
therapies.

The first iteration in the development of cancer immunotherapy treatment regimens—the use of nonspecific cytokine treatments that included IL-2 and interferon—created an important treatment option for patients with metastatic renal cell carcinoma that remained the mainstay of treatment for nearly 15 years. Until the approvals of the first antiangiogenic VEGF tyrosine kinase inhibitors in 2005 and 2006, high-dose, bolus intravenous IL-2 was the only treatment approved by the U.S. Food and Drug Administration (FDA) for patients with metastatic renal cell carcinoma, an approval granted in 1992 for its ability to produce durable complete responses in a small subset of patients.

Data from seven phase II clinical trials of IL-2 involving a total of 255 patients with metastatic renal cell carcinoma demonstrated an overall response rate of 15%, which included complete response in 7% of patients and partial response in 8% of patients.2,3 Subsequent modern trials with high-dose, bolus IL-2 such as the Cytokine Working Group’s Select trial, have demonstrated response rates nearing 30% and of greater quality and durability.4 Taken together, these studies clearly demonstrated the benefit that immunotherapy can provide for a subset of patients with metastatic renal cell carcinoma.

Although immunotherapy was once the standard of care, the advent of oral therapies that target angiogenesis and other signal transduction pathways and that produced significant clinical benefits in larger patient subsets prompted a reassessment of the role of immunotherapy in advanced renal cell carcinoma. Due to their broad activity and relatively tolerable toxicity profiles, the last 10 years saw a shift away from the use of cytokine-based treatment of metastatic renal cell carcinoma to the use of these newer targeted oral therapies.

In contrast to the results achieved with IL-2, the cytostatic molecularly targeted therapies (eg, sorafenib, sunitinib, everolimus) do not produce durable remissions when therapy is discontinued, and treatment resistance inevitably develops. In recent years, however, an improved understanding of immunology and tumor biology has led to the development of novel immunotherapeutic treatment strategies that include vaccines such as sipuleucel-T (Provenge), the first and thus far only therapeutic cancer vaccine to achieve FDA approval (in 2010), as well as immune checkpoint inhibitors (eg, ipilimumab [Yervoy] approved in 2011, nivolumab), and the adoptive transfer of engineered T cells (eg, tumor-infiltrating lymphocytes, or T cells engineered to express a recombinant T-cell receptor [TCR] or chimeric antigen receptor [CAR]).5

It is the latter two strategies in particular that have generated newfound enthusiasm for cancer immunotherapy.

Checkpoint Blockade to Eliminate Immune Suppression

Please describe the concept of checkpoint blockade in renal cell carcinoma therapy.

Since the groundbreaking work of James Allison and others in the 1990s unravelling the molecular mechanisms governing the host response to tumors and identifying the signaling pathways involved in limiting the immune response, a successful therapeutic strategy has emerged based on the development of various agents that enhance the anticancer immune response by “taking the brakes off” these immunosuppressive, inhibitory (“checkpoint”) pathways.6

To date, the most clinically important checkpoint molecules mediating tumor-induced immune suppression are cytotoxic T-lymphocyte antigen-4 (CTLA-4) as well as the programmed death-1 (PD-1) receptor and its ligands. CTLA-4 acts as a signal dampener acting primarily within the lymph nodes to regulate the early activation of naive and memory T cells. PD-1, by contrast, is induced on T cells after activation in response to inflammatory signals and limits T-cell function in peripheral tissues.7

The anti–CTLA-4 monoclonal antibody ipilimumab improved survival in a phase III trial in patients with metastatic melanoma8 and was subsequently approved by the FDA in 2011 for the treatment of patients with that indication. However, the fully human anti–PD-1 monoclonal antibody BMS-936558/MDX-1106/ONO-4538 (nivolumab), has already demonstrated impressive antitumor activity in phase I/Ib studies of not only renal cell carcinoma, but also castration-resistant prostate cancer, non–small cell lung cancer, and colorectal cancer.9

What is notable about the clinical results using checkpoint inhibitor therapy is the high level of antitumor activity (eg, the spectrum of tumors that appear to be responsive, and the durability of the responses). In advanced melanoma, for example, investigators have found reductions in tumor size of more than 80% in the majority of patients in one study,10 and a 4-year survival rate of approximately 20% in another.8

Adoptive Immunotherapy

How has adoptive immunotherapy been used in renal cell carcinoma treatment, and where you think the new era of treating metastatic renal cell carcinoma is headed?

Adoptive immunotherapy refers to the passive transfer of immune cells with antitumor activity into a tumor-bearing host. Currently, there are three main strategies that have been extensively studied for the adoptive immunotherapy of cancer.

The first use of adoptive immunotherapy of cancer was based on the use of tumor-infiltrating lymphoctyes. The antitumor activity of tumor-infiltrating lymphoctyes is thought to be mediated through interaction between the tumor cell and the T-cell receptor and is major histocompatibility complex (MHC)-restricted.11

Early trials of tumor-infiltrating lymphoctyes in metastatic renal cell carcinoma such as the UCLA experience combining tumor-infiltrating lymphoctyes with low-dose IL-2 plus interferon demonstrated the feasibility of this approach, with an intriguing 35% response rate that includes durable remissions.12 However, a subsequent multicenter phase III trial randomly assigning subjects with metastatic renal cell carcinoma to low-dose IL-2 alone vs low-dose IL-2 plus tumor-infiltrating lymphoctyes was negative.13 After randomization of 160 subjects, intent-to-treat analysis revealed response rates of 9.9% vs 11.4% (IL-2 vs IL-2/tumor-infiltrating lymphoctyes).

Nevertheless, this negative trial was fraught with difficulty, especially with regard to the successful preparation of tumor-infiltrating lymphoctyes at a centralized facility. Of the subjects randomly assigned to the tumor-infiltrating lymphoctye arm, 41% did not receive these cells because of processing difficulties.

To date, tumor-infiltrating lymphoctye therapy has proven effective only in the treatment of metastatic melanoma. This limitation has arisen primarily because it has not proven to be possible to consistently and successfully isolate, culture, establish, and expand large populations of tumor-reactive T cells with anticancer activity from the tumors of the majority of patients having other tumor types.

The two other strategies of adoptive T-cell immunotherapy have found ways to circumvent this problem.14 T-cell receptor therapy utilizes patients’ easily acquired peripheral T cells, which are then genetically engineered using viral vectors to transduce and express a specific recombinant T-cell receptor capable of recognizing a specified tumor antigen (eg, CAIX, MART-1, NY-ESO). Clinical trials of T-cell receptor therapy have shown unexpected anticancer activity in a number of solid tumor indications including melanoma and other unanticipated diseases such as colorectal cancer and synovial sarcoma.15,16

Although T-cell receptor–transduced T cells are engineered to express a particular T-cell receptor, they still require tumor recognition in the context of MHC restriction, and therefore, they can be used only in a subset of patients. They are vulnerable to the well-known mechanism of tumor evasion of immune recognition through MHC downregulation.

The third strategy for adoptive T-cell therapy circumvents these issues as well. In this option, peripherally acquired T cells are transduced by a chimeric antigen receptor that combines the variable region of an antibody domain with a CD3/T-cell signaling molecule. More recent second- and third-generation chimeric antigen receptor iterations include other costimulatory molecules such as CD28 and 4-IBB.17

The ability of the chimeric antigen receptor to recognize tumor antigens and engage native T-cell receptor–mediated activation is derived from non–MHC-restricted antibody binding, which is capable of antigen recognition and binding with exquisite sensitivity. Moreover, like T-cell receptor trials, clinical trials of modern chimeric antigen receptor strategies have demonstrated great potential across a spectrum of tumor types, with the greatest success thus far being seen in a variety of hematologic malignancies expressing the CD19 antigen.18,19

The use of T-cell receptor and chimeric antigen receptor technology has only just begun to be applied to renal cell carcinoma.20 The next decade will witness a new renaissance in the use of immunotherapy of renal cell carcinoma. This will be based on combinations of nonspecific immunotherapies such as IL-2, targeted immunotherapies utilizing engineered T cells, augmentation of the anticancer immune response through the use of immune checkpoint blockade, and likely even combinatory approaches simultaneously using standard molecularly targeted approaches. ■

Disclosure: Drs. Pantuck and Belldegrun are scientific founders and equity holders of Kite Pharma Inc, a Los Angeles–based biotechnology company dedicated to the development of adoptive T-cell receptor and chimeric antigen receptor engineered T-cell cancer therapies. Dr. Belldegrun is Executive/Director of Kite Pharma.

References

1. Couzin-Frankel J: Breakthrough of the year 2013: Cancer immunotherapy. Science 342:1432-1433, 2013.

2. Fyfe G, Fisher RI, Rosenberg SA, et al: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13:688-696, 1995.

3. Fisher RI, Rosenberg SA, Fyfe G: Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 6(suppl 1): S55-S57, 2000.

4. McDermott DF, Ghebremichael MS, Signoretti S, et al: The high-dose aldesleukin (HD-IL-2) “SELECT” trial in patients with metastatic renal cell carcinoma. J Clin Oncol 28(15s): Abstract 4514, 2010.

5. Drakaki A, McDermott DF: Novel immunotherapies in GU malignancies. Curr Oncol Rep 15:224-231, 2013.

6. McDermott DM, Atkins M: PD-1 as a potential target in cancer therapy. Cancer Medicine 2:662-673, 2013.

7. Topalian, SL, Drake CG, Pardoll DM: Targeting the PD-1/B7-H1 (PDL-1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24:207-212, 2012.

8. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010.

9. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012.

10. Wolchok JD, Kluger H, Callahan MK, et al: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122-133, 2013.

11. Finke JH, Rayman P, Hart L, et al: Characterization of tumor infiltrating lymphocyte subsets from human renal cell carcinoma: Specific reactivity defined by cytotoxicity, interferon gamma secretion, and proliferation. J Immunother Emphasis Tumor Immunol 15:91-104, 1994.

12. Figlin RA, Pierce WC, Kaboo R, et al: Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2, and cytokine-primed or CD8(+) selected tumor infiltrating lymphocytes from primary tumor. J Urol 158:740-745, 1997.

13. Figlin RA, Thompson JA, Bukowski RM, et al: Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 17:2521-2529, 1999.

14. Humphries C: Adoptive cell therapy: Honing that killer instinct. Nature 504:S13-S15, 2013.

15. Robbins PF, Morgan RA, Feldman SA, et al: Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29:917-924, 2011.

16. Parkhurst MR, Yang JC, Langan RC, et al: T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 19:620-626, 2011.

17. Sampson JH, Choi BD, Sanchez-Perez L, et al: EGFRvIII mCAR-mediated T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res 20:972-984, 2013.

18. Kochenderfer JN, Dudley ME, Feldman SA, et al: B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric antigen receptor transduced T cells. Blood 119:2709-2720, 2012.

19. Porter DL, Levine BL, Kalos M, et al: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725-733, 2011.

20. Lamers CH, Sleijfer S, Vulto AG, et al: Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: First clinical experience. J Clin Oncol 24:e20-e22, 2006.

 


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