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group_3_presentation_2_-_oncolytic_immunotherapy [2016/03/11 22:18] domazee |
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 maturation of the DCs and their migration to the lymph nodes allows for induction of effector functions against tumour cells.<sup>13</sup> CD4 and cytotoxic CD8 T-cells play important roles in the systemic immune response of oncolytic immunotherapy.<sup>13</sup> | The maturation of the DCs and their migration to the lymph nodes allows for induction of effector functions against tumour cells.<sup>13</sup> CD4 and cytotoxic CD8 T-cells play important roles in the systemic immune response of oncolytic immunotherapy.<sup>13</sup> | ||
| - | <box 22% round right | > {{:tcell_response.png?200|}} </box| Figure 1 - Summary of Local and Systemic Effects in Healthy vs. Tumour Cells (Andtbacka et al., 2015) > | + | <box 22% round right | > {{:tcell_response.png?200|}} </box| Figure 7 - Activation, survival and differentiation signals occur through the interaction of CD4 T cells and dendritic cells (Murphy et al., 2012). > |
| ==Activation of CD4 T-Cells== | ==Activation of CD4 T-Cells== | ||
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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 7 - Summary of Local and Systemic Effects in Healthy vs. Tumour Cells (Andtbacka et al., 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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| Before discussing the studies that were conducted using T-VEC on melanoma patients, it is important to define what melanoma is and give a background on various stages of this cancer. Melanoma is a tumour that starts in melanocytes which is malignant in nature, meaning it is able to spread to other parts of the body. Melanocytes are a type of cell responsible for producing melanin, the pigment that your skin and eyes their respective colors.<sup>25</sup> The skin itself is part of the integumentary system, and is the largest organ in mammals.<sup>25</sup> It covers the entirety of the body, protecting it from external damage via infection, ultraviolet damage and injury. Moreover, it produces vitamin D and maintains body temperature in addition to storing water and fat.<sup>25</sup> Human skin is composed of two primary layers, the dermis and the epidermis. The latter is the outermost layer of the skin, creating a protective barrier over the body’s surface. It is also made up of three types of cells, one of which is melanocytes, found inferior to both squamous and basal cells respectively, at the bottom of the epidermis.<sup>25</sup> Melanoma is the most dangerous form of skin cancer. Interestingly enough, when skin cancer starts in squamous or basal cells, it is called non-melanoma skin cancer. The primary cause of melanoma is ultraviolet light exposure (ex. excessive exposure to sunlight) in those with low levels of melanin.<sup>25</sup> However, unusual moles, health history and poor immune function can also affect the risk of melanoma. Up to 25% of melanoma cases develop directly from moles.<sup>25</sup> Diagnosis occurs through a biopsy of any skin lesions showing symptoms of melanoma. Due to a variety of factors, cells in the skin are often altered and no longer function or grow normally. When melanocytes become atypical they often go undetected because they display precancerous conditions despite not being cancerous.<sup>25</sup> However, there is an increased chance these changes may become cancerous, such as in the presence of an abnormal mole or dysplastic nevus. The most common form of melanoma is superficial spreading melanoma, which occurs on the skin.<sup>25</sup> However, it is possible that melanoma can occur in other parts of the body where it is present such as internal organs (mucosal lentiginous melanoma).<sup>25</sup> | Before discussing the studies that were conducted using T-VEC on melanoma patients, it is important to define what melanoma is and give a background on various stages of this cancer. Melanoma is a tumour that starts in melanocytes which is malignant in nature, meaning it is able to spread to other parts of the body. Melanocytes are a type of cell responsible for producing melanin, the pigment that your skin and eyes their respective colors.<sup>25</sup> The skin itself is part of the integumentary system, and is the largest organ in mammals.<sup>25</sup> It covers the entirety of the body, protecting it from external damage via infection, ultraviolet damage and injury. Moreover, it produces vitamin D and maintains body temperature in addition to storing water and fat.<sup>25</sup> Human skin is composed of two primary layers, the dermis and the epidermis. The latter is the outermost layer of the skin, creating a protective barrier over the body’s surface. It is also made up of three types of cells, one of which is melanocytes, found inferior to both squamous and basal cells respectively, at the bottom of the epidermis.<sup>25</sup> Melanoma is the most dangerous form of skin cancer. Interestingly enough, when skin cancer starts in squamous or basal cells, it is called non-melanoma skin cancer. The primary cause of melanoma is ultraviolet light exposure (ex. excessive exposure to sunlight) in those with low levels of melanin.<sup>25</sup> However, unusual moles, health history and poor immune function can also affect the risk of melanoma. Up to 25% of melanoma cases develop directly from moles.<sup>25</sup> Diagnosis occurs through a biopsy of any skin lesions showing symptoms of melanoma. Due to a variety of factors, cells in the skin are often altered and no longer function or grow normally. When melanocytes become atypical they often go undetected because they display precancerous conditions despite not being cancerous.<sup>25</sup> However, there is an increased chance these changes may become cancerous, such as in the presence of an abnormal mole or dysplastic nevus. The most common form of melanoma is superficial spreading melanoma, which occurs on the skin.<sup>25</sup> However, it is possible that melanoma can occur in other parts of the body where it is present such as internal organs (mucosal lentiginous melanoma).<sup>25</sup> | ||
| - | <box 37% round right | > {{:melanomaiv.png?350|}} </box| Figure 5 - Stage IV melanoma spreading away from the primary site and to other organs in the human body (Winslow, 2008). > | + | <box 37% round right | > {{:melanomaiv.png?350|}} </box| Figure 9 - Stage IV melanoma spreading away from the primary site and to other organs in the human body (Winslow, 2008). > |
| - | ===Stages of Melanoma=== | + | ====Stages of Melanoma==== |
| ==Stage 0: in situ melanoma (99.9% survival)== | ==Stage 0: in situ melanoma (99.9% survival)== | ||
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| ==Stage III (A/B/C): Regional metastasis (24–70% survival)== | ==Stage III (A/B/C): Regional metastasis (24–70% survival)== | ||
| - | *In stage 3 the melanoma may be a variety of thicknesses with or without ulceration. However, one or more of the following is true. Firstly, the cancer has spread to one or more lymph nodes. Secondly, the lymph nodes are matted or joined together. Third, the cancer is in a lymph vessel between the primary tumor and nearby lymph nodes. Fourthly, the cancer is more than 2 centimeters away from the primary tumor. Finally, very small tumors can be located on or underneath the skin, less than 2 centimeters away from the primary tumor. | + | *In stage 3 the melanoma may be a variety of thicknesses with or without ulceration. However, one or more of the following is true. Firstly, the cancer has spread to one or more lymph nodes. Secondly, the lymph nodes are matted or joined together. Third, the cancer is in a lymph vessel between the primary tumour and nearby lymph nodes. Fourthly, the cancer is more than 2 centimeters away from the primary tumour. Finally, very small tumours can be located on or underneath the skin, less than 2 centimeters away from the primary tumour. |
| ==Stage IV: Distant metastasis (7–19% survival)== | ==Stage IV: Distant metastasis (7–19% survival)== | ||
| *In the fourth and final stage of melanoma, the cancer has spread to other parts of the body away from the primary site and the nearby lymph nodes. In most cases, it is common for the cancer to spread to the lungs, liver, and brain or to distant lymph nodes or areas of the skin. However, it is not unheard of for the cancer to spread to places far away from its origin. | *In the fourth and final stage of melanoma, the cancer has spread to other parts of the body away from the primary site and the nearby lymph nodes. In most cases, it is common for the cancer to spread to the lungs, liver, and brain or to distant lymph nodes or areas of the skin. However, it is not unheard of for the cancer to spread to places far away from its origin. | ||
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| ====Study 1: Local and Systemic Immune Response to T-VEC ==== | ====Study 1: Local and Systemic Immune Response to T-VEC ==== | ||
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| === Findings and Conclusions=== | === Findings and Conclusions=== | ||
| - | Researchers compared the frequency of CD4+FoxP3+ regulatory T cells in both the peripheral blood and the tumour microenvironment.<sup>12</sup> In the peripheral blood, there was a higher frequency of Treg cells among patients who were treated with T-VEC compared to healthy donors who did not have melanoma.<sup>12</sup> In addition, there was also a higher frequency of T-reg cells in patients who were treated with T-VEC compared to patients who were not treated with T-VEC in the tumour microenvironment.<sup>12</sup> Therefore, by decreasing the frequency of Treg cells, T-VEC acts to decrease the inhibitory functions these cells on CD4 cells in the tumour microenvironment.<sup>12</sup> Researchers also compared the frequency of CD8+FoxP3+ suppressor T cells in both the peripheral blood and the tumour microenvironment.<sup>12</sup> Again, similar results were found, as there was a higher frequency of Ts cells among patients who were treated with T-VEC compared to healthy donors who did not have melanoma in the peripheral blood.<sup>12</sup> In addition, there was also a higher frequency of Ts cells in patients who were treated with T-VEC compared to patients who were not treated with T-VEC in the tumour microenvironment.<sup>12</sup> Therefore, by decreasing the frequency of Ts cells, T-VEC acts to decrease the inhibitory effects of on the cytotoxicity of CD8 cells in the tumour microenvironment.<sup>12</sup> In addition, to determine the systemic immune effects of T-VEC, the researchers analyzed the frequency of Treg cells in the lesions that received the T-VEC injection and in the lesions that did not receive the injection in the same patients.<sup>12</sup> They then compared the Treg frequencies in lesions of non-vaccinated patients.<sup>12</sup> The results indicated that there was a lower frequency of Treg cells in non-target lesions in vaccinated patients than in lesions of non-vaccinated patients.<sup>12</sup> This ultimately provides evidence that T-VEC is able to decrease the frequency of Treg cells in distant lesions that are not injected.<sup>12</sup> Ultimately, the collective findings of the experiments provided evidence of antigen-specific immunity in both locally injected lesions and distant non-injected tumors.<sup>12</sup> More importantly, these findings are consistent with priming of systemic antitumor immunity and suggest that T-VEC is capable of inducing systemic immunity.<sup>12</sup> | + | Researchers compared the frequency of CD4+FoxP3+ regulatory T cells in both the peripheral blood and the tumour microenvironment.<sup>12</sup> In the peripheral blood, there was a higher frequency of Treg cells among patients who were treated with T-VEC compared to healthy donors who did not have melanoma.<sup>12</sup> In addition, there was also a higher frequency of T-reg cells in patients who were treated with T-VEC compared to patients who were not treated with T-VEC in the tumour microenvironment.<sup>12</sup> Therefore, by decreasing the frequency of Treg cells, T-VEC acts to decrease the inhibitory functions these cells on CD4 cells in the tumour microenvironment.<sup>12</sup> Researchers also compared the frequency of CD8+FoxP3+ suppressor T cells in both the peripheral blood and the tumour microenvironment.<sup>12</sup> Again, similar results were found, as there was a higher frequency of Ts cells among patients who were treated with T-VEC compared to healthy donors who did not have melanoma in the peripheral blood.<sup>12</sup> In addition, there was also a higher frequency of Ts cells in patients who were treated with T-VEC compared to patients who were not treated with T-VEC in the tumour microenvironment.<sup>12</sup> Therefore, by decreasing the frequency of Ts cells, T-VEC acts to decrease the inhibitory effects of on the cytotoxicity of CD8 cells in the tumour microenvironment.<sup>12</sup> In addition, to determine the systemic immune effects of T-VEC, the researchers analyzed the frequency of Treg cells in the lesions that received the T-VEC injection and in the lesions that did not receive the injection in the same patients.<sup>12</sup> They then compared the Treg frequencies in lesions of non-vaccinated patients.<sup>12</sup> The results indicated that there was a lower frequency of Treg cells in non-target lesions in vaccinated patients than in lesions of non-vaccinated patients.<sup>12</sup> This ultimately provides evidence that T-VEC is able to decrease the frequency of Treg cells in distant lesions that are not injected.<sup>12</sup> Ultimately, the collective findings of the experiments provided evidence of antigen-specific immunity in both locally injected lesions and distant non-injected tumors.<sup>12</sup> More importantly, these findings are consistent with priming of systemic anti-tumour immunity and suggest that T-VEC is capable of inducing systemic immunity.<sup>12</sup> |
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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 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). > | ||
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| + | ==== 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. | ||
| - | <box 48% round left | > {{:results_1.png?350|}} </box| Figure 1 - Summary of Local and Systemic Effects in Healthy vs. Tumour Cells (Andtbacka et al., 2015) > | + | ==== Study 3: Phase III OPTiM Clinical Trial ==== |
| - | <box 48% round right | >{{:results_2.png?350|}} </box| Figure 1 - Summary of Local and Systemic Effects in Healthy vs. Tumour Cells (Andtbacka et al., 2015) > | + | 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 ===== | ||
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| 25. What is melanoma? - Canadian Cancer Society. (2011, July 17). Retrieved March 11, 2016, from http://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/melanoma/?region=on | 25. What is melanoma? - Canadian Cancer Society. (2011, July 17). Retrieved March 11, 2016, from http://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/melanoma/?region=on | ||
| + | 26.Senzer, N. N., Kaufman, H. L., Amatruda, T., Nemunaitis, M., Reid, T., Daniels, G., . . . Nemunaitis, J. J. (2009). Phase II Clinical Trial of a Granulocyte-Macrophage Colony-Stimulating Factor-Encoding, Second-Generation Oncolytic Herpesvirus in Patients With Unresectable Metastatic Melanoma. Journal of Clinical Oncology, 27(34), 5763-5771. Retrieved March 11, 2016. | ||
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| + | 27.Andtbacka, R. H., Collichio, F. A., Amatruda, T., Senzer, N., Chesney, J., Delman, K., . . . Kaufman, H. (2014). Final planned overall survival (OS) from OPTiM, a randomized Phase III trial of talimogene laherparepvec (T-VEC) versus GM-CSF for the treatment of unresected stage IIIB/C/IV melanoma (NCT00769704). Journal for ImmunoTherapy of Cancer J Immunother Cancer, 2(Suppl 3). Retrieved March 11, 2016. | ||
