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group_3_presentation_2_-_oncolytic_immunotherapy [2016/03/11 22:42] singhm38 |
group_3_presentation_2_-_oncolytic_immunotherapy [2018/01/25 15:19] (current) |
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| The mechanisms of oncolytic immunotherapy can be broken down into two major effects: the local effects and the systemic effects.<sup>1</sup> The local effects consist of tumour cell lysis.<sup>1</sup> The oncolytic virus (OV) must first selectively target cancer cells and replicate.<sup>1</sup> Next, the tumour cells lyse, thus representing the oncolytic effect.<sup> 1 </sup> Furthermore, the systemic effects include the tumour-specific immune response, which activates antigen presenting immune cells.<sup> 1 </sup> This primes the adaptive immune response and leads to a series of downstream effects that result in death of distant cancerous cells.<sup>2</sup> | The mechanisms of oncolytic immunotherapy can be broken down into two major effects: the local effects and the systemic effects.<sup>1</sup> The local effects consist of tumour cell lysis.<sup>1</sup> The oncolytic virus (OV) must first selectively target cancer cells and replicate.<sup>1</sup> Next, the tumour cells lyse, thus representing the oncolytic effect.<sup> 1 </sup> Furthermore, the systemic effects include the tumour-specific immune response, which activates antigen presenting immune cells.<sup> 1 </sup> This primes the adaptive immune response and leads to a series of downstream effects that result in death of distant cancerous cells.<sup>2</sup> | ||
| - | <box 65% round | > {{:screen_shot_2016-03-10_at_4.12.12_pm.png?650|}} </box| Figure 1 - Summary of local and systemic effects of T-VEC in healthy vs. tumour cells (Andtbacka et al., 2015). > | + | <box 55% round | > {{:screen_shot_2016-03-10_at_4.12.12_pm.png?550|}} </box| Figure 1 - Summary of local and systemic effects of T-VEC in healthy vs. tumour cells (Andtbacka et al., 2015). > |
| ===== Oncolytic Immunotherapy ===== | ===== Oncolytic Immunotherapy ===== | ||
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| - | <box 46% round right | >{{:screen_shot_2016-03-11_at_2.00.21_pm.png?450|}} </box| Figure 2 - Treatment with oncolytic immunotherapy at baseline (left) and at 6 months (right) (IMWJ, 2010).> | + | <box 40% round right | >{{:screen_shot_2016-03-11_at_2.00.21_pm.png?400|}} </box| Figure 2 - Treatment with oncolytic immunotherapy at baseline (left) and at 6 months (right) (IMWJ, 2010).> |
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| The activation of cytotoxic CD8 cells occurs through two methods. The first method of activation of CD8 cells occurs in a very similar manner to the CD4 cells. In this case, the CD8 cell co-receptor binds to the peptide:MHC Class I complex.<sup>13</sup> The binding of the B7 co-stimulatory ligand to the CD28 co-stimulatory receptor is required for CD8 cell activation as well.<sup>13</sup> When CD8 cells are activated by these intracellular interaction, they synthesize interleukin (IL) -2, which is a cytokine, and the IL-2 receptor.<sup>13</sup> This subsequent interaction allows for proliferation and differentiation of CD8 cells.<sup>13</sup> If this process does not provide sufficient co-stimulation, the CD4 effector cells can help to activate naïve virus-specific CD8 cells as well.<sup>13</sup> In this case, the DC interacts with both CD4 and CD8 T-cells through interactions with the peptide:MHC Class II complex and the peptide:MHC Class I complex, respectively.<sup>13</sup> In addition, the IL-2 cytokine that is secreted by the CD4 cell binds to the IL-2 receptor on the CD8 cell, which leads to proliferation and differentiation of the CD8 cell.<sup>13</sup> The activated cytotoxic CD8 cells can now exit the lymph nodes and travel throughout the body to kill distant tumour cells. | The activation of cytotoxic CD8 cells occurs through two methods. The first method of activation of CD8 cells occurs in a very similar manner to the CD4 cells. In this case, the CD8 cell co-receptor binds to the peptide:MHC Class I complex.<sup>13</sup> The binding of the B7 co-stimulatory ligand to the CD28 co-stimulatory receptor is required for CD8 cell activation as well.<sup>13</sup> When CD8 cells are activated by these intracellular interaction, they synthesize interleukin (IL) -2, which is a cytokine, and the IL-2 receptor.<sup>13</sup> This subsequent interaction allows for proliferation and differentiation of CD8 cells.<sup>13</sup> If this process does not provide sufficient co-stimulation, the CD4 effector cells can help to activate naïve virus-specific CD8 cells as well.<sup>13</sup> In this case, the DC interacts with both CD4 and CD8 T-cells through interactions with the peptide:MHC Class II complex and the peptide:MHC Class I complex, respectively.<sup>13</sup> In addition, the IL-2 cytokine that is secreted by the CD4 cell binds to the IL-2 receptor on the CD8 cell, which leads to proliferation and differentiation of the CD8 cell.<sup>13</sup> The activated cytotoxic CD8 cells can now exit the lymph nodes and travel throughout the body to kill distant tumour cells. | ||
| - | <box 42% round centre | >{{:picture1.png?400|}} </box| Figure 8 - CD4 T cells can assist with the activation of CD8 T cells through the interaction of IL-2 on the CD8 T cell (Parham, 2015). > | + | <box 31% round centre | >{{:picture1.png?300|}} </box| Figure 8 - CD4 T cells can assist with the activation of CD8 T cells through the interaction of IL-2 on the CD8 T cell (Parham, 2015). > |
| === Cytotoxicity of CD8 Cells=== | === Cytotoxicity of CD8 Cells=== | ||
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| - | ====Clinical Trials==== | ||
| - | ==Phase 2== | ||
| - | In 2009, 50 patients with advanced melanoma were treated with T-VEC and evaluated via RECIST (Response Evaluation Criteria In Solid Tumours).<sup>26</sup> This is a set of published rules that define when tumours in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. Following treatment, the following results were observed. Approximately16% of patients experienced a complete response, indicated by a disappearance of all target lesions.<sup>26</sup> An additional 10% experienced a partial response, characterized by a minimum 30% decrease in the size of target lesions, taking as reference the baseline longest diameter (LD) for an overall response rate of 26%.<sup>26</sup> Furthermore, 20% of the patients, a small but critical portion, maintained a stable condition for 20 months.<sup>26</sup>They experienced neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Overall, 54% of patients survived until Year 1 while 52% survived until Year 2 under treatment with T-VEC.<sup>26</sup> Additionally, a few patients exhibited initial disease progression before eventually responding by generating the full immune response. Finally, responses were observed in both injected and uninjected tumours (including those in visceral organs), demonstrating systemic immunotherapeutic effects. | ||
| - | ==Phase III OPTiM== | ||
| - | In a global, open-label trial, 430 patients with unresectable stage IIIB, IIIC or IV melanoma were treated with either T-VEC or subcutaneously administered GM-CSF.<sup>27</sup> Patients underwent outcome-adaptive randomization via a 2:1 fixed ratio, to create twice as many patients randomly assigned to T-VEC treatment. The primary endpoint was durable response rate (DRR), defined as a complete or partial tumor response lasting at least 6 months and starting within 12 months of treatment.<sup>27</sup> The median time to respond was 4.1 months, and more than half of the patients experienced approximately a 25% or greater increase in the size of lesions or appearance of new lesions before achieving a response.<sup>27</sup> This pseudo pattern is consistent with other immunotherapy's and illustrates the importance of continuing treatment in clinically stable patients even if individual lesions increase in size or new lesions develop. T-VEC showed superior benefits to metastatic melanoma as outlined by the DRR achieved in 16% of patients receiving T-VEC compared with only 2% in the GM-CSF control group.<sup>27</sup> The greatest benefit was seen in stage IIIB or IIIC melanoma, with 33% of T-VEC patients maintaining a DRR in comparison to 0% with GM-CSF. The objective response rate (any response) with T-VEC was 32%, with 17% of patients experiencing a complete response, characterized by a complete disappearance of melanoma throughout the body.<sup>27</sup> Ultimately, this showed that T-VEC has a systemic immune effect that destroys distant, uninjected tumours. | ||
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| <box 48% round left | > {{:results_1.png?350|}} </box| Figure 10 - A decrease in frequency of Treg cells in patients who received the T-VEC injection compared to patients who did not receive the T-VEC injection (Kaufman et al., 2010). > | <box 48% round left | > {{:results_1.png?350|}} </box| Figure 10 - A decrease in frequency of Treg cells in patients who received the T-VEC injection compared to patients who did not receive the T-VEC injection (Kaufman et al., 2010). > | ||
| <box 48% round right | >{{:results_2.png?350|}} </box| Figure 11 - A decrease in frequency of Ts cells in patients who received the T-VEC injection compared to patients who did not receive the T-VEC injection (Kaufman et al., 2010). > | <box 48% round right | >{{:results_2.png?350|}} </box| Figure 11 - A decrease in frequency of Ts cells in patients who received the T-VEC injection compared to patients who did not receive the T-VEC injection (Kaufman et al., 2010). > | ||
| + | |||
| + | ==== Study 2: Phase II Clinical Trial ==== | ||
| + | In 2009, 50 patients with advanced melanoma were treated with T-VEC and evaluated via RECIST (Response Evaluation Criteria In Solid Tumours).<sup>26</sup> This is a set of published rules that define when tumours in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. Following treatment, the following results were observed. Approximately16% of patients experienced a complete response, indicated by a disappearance of all target lesions.<sup>26</sup> An additional 10% experienced a partial response, characterized by a minimum 30% decrease in the size of target lesions, taking as reference the baseline longest diameter (LD) for an overall response rate of 26%.<sup>26</sup> Furthermore, 20% of the patients, a small but critical portion, maintained a stable condition for 20 months.<sup>26</sup>They experienced neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Overall, 54% of patients survived until Year 1 while 52% survived until Year 2 under treatment with T-VEC.<sup>26</sup> Additionally, a few patients exhibited initial disease progression before eventually responding by generating the full immune response. Finally, responses were observed in both injected and uninjected tumours (including those in visceral organs), demonstrating systemic immunotherapeutic effects. | ||
| + | |||
| + | ==== Study 3: Phase III OPTiM Clinical Trial ==== | ||
| + | In a global, open-label trial, 430 patients with unresectable stage IIIB, IIIC or IV melanoma were treated with either T-VEC or subcutaneously administered GM-CSF.<sup>27</sup> Patients underwent outcome-adaptive randomization via a 2:1 fixed ratio, to create twice as many patients randomly assigned to T-VEC treatment. The primary endpoint was durable response rate (DRR), defined as a complete or partial tumor response lasting at least 6 months and starting within 12 months of treatment.<sup>27</sup> The median time to respond was 4.1 months, and more than half of the patients experienced approximately a 25% or greater increase in the size of lesions or appearance of new lesions before achieving a response.<sup>27</sup> This pseudo pattern is consistent with other immunotherapy's and illustrates the importance of continuing treatment in clinically stable patients even if individual lesions increase in size or new lesions develop. T-VEC showed superior benefits to metastatic melanoma as outlined by the DRR achieved in 16% of patients receiving T-VEC compared with only 2% in the GM-CSF control group.<sup>27</sup> The greatest benefit was seen in stage IIIB or IIIC melanoma, with 33% of T-VEC patients maintaining a DRR in comparison to 0% with GM-CSF. The objective response rate (any response) with T-VEC was 32%, with 17% of patients experiencing a complete response, characterized by a complete disappearance of melanoma throughout the body.<sup>27</sup> Ultimately, this showed that T-VEC has a systemic immune effect that destroys distant, uninjected tumours. | ||
| ===== Negative Implications of Oncolytic Immunotherapy ===== | ===== Negative Implications of Oncolytic Immunotherapy ===== | ||
