Role of Antigen Spread and Distinctive Characteristics of Immunotherapy in Cancer Treatment

Abstract

Immunotherapy is an important breakthrough in cancer. US Food and Drug Administration-approved immunotherapies for cancer treatment (including, but not limited to, sipuleucel-T, ipilimumab, nivolumab, pembrolizumab, and atezolizumab) substantially improve overall survival across multiple malignancies. One mechanism of action of these treatments is to induce an immune response against antigen-bearing tumor cells; the resultant cell death releases secondary (nontargeted) tumor antigens. Secondary antigens prime subsequent immune responses (antigen spread). Immunotherapy-induced antigen spread has been shown in clinical studies. For example, in metastatic castration-resistant prostate cancer patients, sipuleucel-T induced early immune responses to the immunizing antigen (PA2024) and/or the target antigen (prostatic acid phosphatase). Thereafter, most patients developed increased antibody responses to numerous secondary proteins, several of which are expressed in prostate cancer with functional relevance in cancer. The ipilimumab-induced antibody profile in melanoma patients shows that antigen spread also occurs with immune checkpoint blockade. In contrast to chemotherapy, immunotherapy often does not result in short-term changes in conventional disease progression end points (eg, progression-free survival, tumor size), which may be explained, in part, by the time taken for antigen spread to occur. Thus, immune-related response criteria need to be identified to better monitor the effectiveness of immunotherapy. As immunotherapy antitumor effects take time to evolve, immunotherapy in patients with less advanced cancer may have greater clinical benefit vs those with more advanced disease. This concept is supported by prostate cancer clinical studies with sipuleucel-T, PSA-TRICOM, and ipilimumab. We discuss antigen spread with cancer immunotherapy and its implications for clinical outcomes.

Figure 1.

The process of antigen spread. A) An initial immune response is prompted following immunotherapy, releasing other antigens from dying tumor cells. B) Dendritic cells act as antigen-presenting cells (APCs), processing the “free” antigens, including neoantigens, and presenting these to T-cells. C) The APCs prime T-cells specific to antigens released from the tumor cells, increasing the breadth of the immune response. D) The newly activated tumor-specific T-cells form in greater concentration and variation. E) The activated T-cells then attack the tumor cells. Thus, while the initial therapy may target one antigen, a broader adaptive antitumor immune response may ensue. MUC-1 = mucin 1; PAP = prostatic acid phosphatase; PSA = prostate-specific antigen; PSCA = prostate stem cell antigen.

Figure 2.

Antigen spread following treatment with immunotherapy (36). Adapted (with permission of Springer) from: Jochems C, Schlom J, Gulley JL. Novel technologies for vaccine development. TRICOM poxviral-based vaccines for the treatment of cancer. In: Lukashevich IS, Shirwan H, eds. Vienna: Springer; 2014:291–328. Original caption: Fig. 10. 1 Schematic overview of TRICOM vaccines showing the tumor antigen gene and the genes for the three costimulatory molecules LFA-3, ICAM-1, and B7-1 that are inserted within the virus. The vaccine is prepared and administered “off the shelf.” 1: Subcutaneous administration leads to antigen uptake by antigen-presenting cells (APC) in the skin. 2: Antigen presentation occurs in the draining lymph nodes, activating antigen-specific T cells. 3: Tumor sites are attacked by antigen-specific cytotoxic (CD8+) T cells. 4: Tumor cell lysis leads to cross-presentation of multiple tumor antigens in the draining lymph nodes (antigen spread/antigen cascade). 5: Antigen cascade leads to activation of additional antigen-specific T-cells, which increases the breadth and quite possibly the clinical activity of the antitumor response.

Figure 3.

The anticancer activity of immunotherapy increases over time. Schematic representing progression and broadening of response over time following treatment with cancer-targeting immunotherapy. Antigen spread leads to more relevant targets (eg, neoantigens) for a given patient, and this highly individualized precision response could lead to improved clinical activity. Furthermore, with subsequent treatment, the immune response may be further boosted as tumor cells are killed or modulated in an immunogenic manner, which translates into improving clinical activity over time. OS = overall survival; PSA = prostate-specific antigen; TDRP = time to disease-related pain; TOFA = time to first opioid analgesic.

Figure 4.

Tumor growth rates with immunotherapy (vaccine) and chemotherapy (cytotoxic therapy). A) Tumor growth rate with no therapy (dotted black line), with cytotoxic therapy (blue line), and with vaccine (red line), demonstrating the slow yet prolonged response with immunotherapy resulting from immune response activation (red line) and a short-term tumor reduction with chemotherapy (blue line). B) Initiating immunotherapy in early-stage disease may enhance the effects of immunotherapy (line b), whereas in later-stage disease the effects could be minimal (line a). Green arrows denote treatment initiation; crosses denote death (60). Adapted (with permission of Oxford University Press) from: Schlom J. Therapeutic cancer vaccines: Current status and moving forward. J Natl Cancer Inst. 2012;104(8):599–613.