Dr. Antonella Vitiello, who is the company’s Chief Executive Officer and Chief Scientific Officer, founded PersImmune, Inc. in 2010 with the mission of developing precision cancer immunotherapy tailored to each patient. Dr. Vitiello’s career as a ground-breaking cancer researcher and her own successful fight against cancer drive the company’s passion for developing safe and effective cancer therapies that preserve the patient’s quality of life and avoid the devastating side effects of currently available cancer treatments.
Q: Tell us about the origins of PersImmune.
A: I founded PersImmune in 2010, thanks to the great generosity and trust of our family friends, John and Rafaela Belanich. They convinced me to start this company after I was diagnosed and treated for ovarian cancer in 2009. My treatment consisted of surgery and chemotherapy, which gave me debilitating side effects and left me with renal impairment. The type of ovarian cancer I had was very rare, meaning that if I had a relapse, there was no data available that would direct possible therapies to select. Because I am an immunologist, I decided that in case of a relapse, I would forgo chemotherapy and, instead, try adoptive transfer with cancer-specific T cells based on a protocol I had developed while at J&J1 in collaboration with the bone marrow transplantation unit at the University of Pavia in Italy. Therefore, I went to Pavia for leukapheresis and had my white blood cells cryopreserved. Thankfully, I did not relapse, and my cells are still cryopreserved. At this time, John and Rafaela Belanich thought that if I was so convinced about the approach that I would use it on myself, it would be a good investment opportunity for starting a company here in the United States. And so, in 2010, we opened our first lab. Three years later, the field of immunotherapy exploded, and we decided to continue working on our approach and pursue a clinical trial. We chose myelodysplastic syndrome as our proof-of-concept disease, as MDS seemed to have the right requisites to indicate that adoptive transfer of a patient’s own T cells (or the T cells of an HLA-matched donor) that are specific for the mutations in the cancer cell could treat the patient’s cancer. In fact, we selected MDS for several reasons. First, MDS is an uncommon disease for which the only curative intervention is bone marrow transplantation, an intervention that not all patients qualify for. Second, working with MDS allows us to obtain and store the tumor cells for the very important validation that the neopeptide-specific T cells can kill the cancer cells. Finally, because it is a hematologic disease, it is possible to verify effectiveness by measuring the disappearance of the relevant mutations at different times after the treatment through simple blood collections. At present, we are growing these cancer-mutation-specific T cells in vitro, expanding them, and infusing them back into the patient. We are currently in a Phase 1 clinical trial, testing dose escalation, which involves increasing the number of T cells to determine the number of T cells that can be transferred into the patient safely. Even though the point of the trial is to confirm safety, we plan to simultaneously measure the effectiveness of these expanded T cells in killing the cancer cells.
Q: Tell us about the clinical trial.
A: This is an FDA- and Human Subjects-approved Phase 1 clinical trial that is designed to test the safety and tolerability of our patient-specific, immunized T cell product, called PACTN. So far, we have treated three patients with the lowest dose. They all tolerated the infusion and the infused cells appear to be functioning. One patient died from pre-existing heart disease, but the other two patients that we infused are doing well. In one of the two, first-line treatment had failed, and once that happens, patients are given a survival rate of 6 months. However, both of our patients, more than 17 months after infusion, are not only still alive but also enjoying a good quality of life. We need to do more work to establish the best dose of the T cells, their effectiveness, and the length of time they persist in the patient.
Q: Tell us about the timeline of the PACTN process.
A: Once a patient is diagnosed with high-risk myelodysplastic disease and the doctor gives consent for the patient’s participation in the trial, an apheresis is performed—a collection of blood from the individual containing a high number of T cells. From the apheresis, we also isolate tumor stem cells, which help us determine the effectiveness (tumor killing) of the T cell product that we obtain at the end of the manufacturing. After separating T cells, tumor cells, and monocytes, we sequence both the tumor cells and the T cells to identify the mutations that are unique to the tumor cells. We then synthesize peptides that are equivalent to the mutations and stimulate the patient's T cells in vitro so that the T cells “learn” to recognize these peptides that are expressed on the tumor cells. We expand this collection of specialized T cells for infusion. Right now, the entire process of apheresis collection and production takes 4 to 6 months, a time frame that works well for patients who undergo standard of care hypomethylating (HMA) chemotherapy as a first-line treatment, which is typically a 6 month regimen. Therefore, we are ready with the cells for infusion when they finish their chemotherapy. However, patients can still enroll in the PACTN clinical trial if they refuse standard of care HMA therapy; in this instance, we might be able to shorten the process to just 3 months. In addition, once we establish the safety of PACTN, it can be investigated in a wide variety of other, lower risk patients.
Q: What have you seen in patient reactions to date?
A: All patients to date have tolerated the infusion well and have had no significant adverse effects after 6 to 12 months. This suggests to us that patients will also tolerate higher cell doses.
Q: Do you think this process will work for other cancers?
A: From all the patients tested thus far, we have obtained T cells specific for at least two mutations that are capable of killing the tumor cell lines. This is a great result since other kinds of immunotherapies tested (for example, checkpoint blockade) have not worked in patients with MDS. In addition, since acute myeloid leukemia is very similar to MDS, the same process should work for AML. Also, we believe that it is very important to test the T cells for recognition of the tumor, because some peptide-specific responses do not kill the tumor cell. As for applying this process to treat other types of cancer, we have not yet worked with solid tumors, so we don’t know how challenging they will be. The main difficulty I anticipate is growing tumor cell lines in vitro, which will be necessary to validate their sensitivity to the killing mediated by the infused T cells.
Q: It sounds like you are identifying issues that need to be overcome in order to advance the range of tumors that may respond to this therapy and also the specificity of the T cells for the tumor?
A: Absolutely. We look forward to testing other tumor types, both other blood cancers and also solid tumors. Very importantly, the specificity of the T cell for the each tumor needs to be established prior to infusion.
Q: With this level of specificity, could adoptive transfer of specialized T cells become a non-toxic cancer treatment?
A: Yes! For adoptive neoantigen-specific T cell therapy to work efficiently and reliably—and I have no doubt that it will work—we will need to further the technology. We need to find a way of understanding why sometimes T cells kill the peptide and not the tumor, and we absolutely need to industrialize the process, which right now is very cumbersome. But once the principle is proven, the technology will evolve. It is a question only of when. I am certain that adoptive transfer of T cells will become the therapy of choice. Ideally, we should be capable of preparing the patient's cells in vitro for infusion and expand them in vivo by subsequent vaccination.
1 Montagna D, Maccario R, Locatelli F, et al. Ex vivo priming for long-term maintenance of antileukemia human cytotoxic T cells suggests a general procedure for adoptive immunotherapy. Blood. 2001;98(12):3359-3366.
Q: Tell us about the origins of PersImmune.
A: I founded PersImmune in 2010, thanks to the great generosity and trust of our family friends, John and Rafaela Belanich. They convinced me to start this company after I was diagnosed and treated for ovarian cancer in 2009. My treatment consisted of surgery and chemotherapy, which gave me debilitating side effects and left me with renal impairment. The type of ovarian cancer I had was very rare, meaning that if I had a relapse, there was no data available that would direct possible therapies to select. Because I am an immunologist, I decided that in case of a relapse, I would forgo chemotherapy and, instead, try adoptive transfer with cancer-specific T cells based on a protocol I had developed while at J&J1 in collaboration with the bone marrow transplantation unit at the University of Pavia in Italy. Therefore, I went to Pavia for leukapheresis and had my white blood cells cryopreserved. Thankfully, I did not relapse, and my cells are still cryopreserved. At this time, John and Rafaela Belanich thought that if I was so convinced about the approach that I would use it on myself, it would be a good investment opportunity for starting a company here in the United States. And so, in 2010, we opened our first lab. Three years later, the field of immunotherapy exploded, and we decided to continue working on our approach and pursue a clinical trial. We chose myelodysplastic syndrome as our proof-of-concept disease, as MDS seemed to have the right requisites to indicate that adoptive transfer of a patient’s own T cells (or the T cells of an HLA-matched donor) that are specific for the mutations in the cancer cell could treat the patient’s cancer. In fact, we selected MDS for several reasons. First, MDS is an uncommon disease for which the only curative intervention is bone marrow transplantation, an intervention that not all patients qualify for. Second, working with MDS allows us to obtain and store the tumor cells for the very important validation that the neopeptide-specific T cells can kill the cancer cells. Finally, because it is a hematologic disease, it is possible to verify effectiveness by measuring the disappearance of the relevant mutations at different times after the treatment through simple blood collections. At present, we are growing these cancer-mutation-specific T cells in vitro, expanding them, and infusing them back into the patient. We are currently in a Phase 1 clinical trial, testing dose escalation, which involves increasing the number of T cells to determine the number of T cells that can be transferred into the patient safely. Even though the point of the trial is to confirm safety, we plan to simultaneously measure the effectiveness of these expanded T cells in killing the cancer cells.
Q: Tell us about the clinical trial.
A: This is an FDA- and Human Subjects-approved Phase 1 clinical trial that is designed to test the safety and tolerability of our patient-specific, immunized T cell product, called PACTN. So far, we have treated three patients with the lowest dose. They all tolerated the infusion and the infused cells appear to be functioning. One patient died from pre-existing heart disease, but the other two patients that we infused are doing well. In one of the two, first-line treatment had failed, and once that happens, patients are given a survival rate of 6 months. However, both of our patients, more than 17 months after infusion, are not only still alive but also enjoying a good quality of life. We need to do more work to establish the best dose of the T cells, their effectiveness, and the length of time they persist in the patient.
Q: Tell us about the timeline of the PACTN process.
A: Once a patient is diagnosed with high-risk myelodysplastic disease and the doctor gives consent for the patient’s participation in the trial, an apheresis is performed—a collection of blood from the individual containing a high number of T cells. From the apheresis, we also isolate tumor stem cells, which help us determine the effectiveness (tumor killing) of the T cell product that we obtain at the end of the manufacturing. After separating T cells, tumor cells, and monocytes, we sequence both the tumor cells and the T cells to identify the mutations that are unique to the tumor cells. We then synthesize peptides that are equivalent to the mutations and stimulate the patient's T cells in vitro so that the T cells “learn” to recognize these peptides that are expressed on the tumor cells. We expand this collection of specialized T cells for infusion. Right now, the entire process of apheresis collection and production takes 4 to 6 months, a time frame that works well for patients who undergo standard of care hypomethylating (HMA) chemotherapy as a first-line treatment, which is typically a 6 month regimen. Therefore, we are ready with the cells for infusion when they finish their chemotherapy. However, patients can still enroll in the PACTN clinical trial if they refuse standard of care HMA therapy; in this instance, we might be able to shorten the process to just 3 months. In addition, once we establish the safety of PACTN, it can be investigated in a wide variety of other, lower risk patients.
Q: What have you seen in patient reactions to date?
A: All patients to date have tolerated the infusion well and have had no significant adverse effects after 6 to 12 months. This suggests to us that patients will also tolerate higher cell doses.
Q: Do you think this process will work for other cancers?
A: From all the patients tested thus far, we have obtained T cells specific for at least two mutations that are capable of killing the tumor cell lines. This is a great result since other kinds of immunotherapies tested (for example, checkpoint blockade) have not worked in patients with MDS. In addition, since acute myeloid leukemia is very similar to MDS, the same process should work for AML. Also, we believe that it is very important to test the T cells for recognition of the tumor, because some peptide-specific responses do not kill the tumor cell. As for applying this process to treat other types of cancer, we have not yet worked with solid tumors, so we don’t know how challenging they will be. The main difficulty I anticipate is growing tumor cell lines in vitro, which will be necessary to validate their sensitivity to the killing mediated by the infused T cells.
Q: It sounds like you are identifying issues that need to be overcome in order to advance the range of tumors that may respond to this therapy and also the specificity of the T cells for the tumor?
A: Absolutely. We look forward to testing other tumor types, both other blood cancers and also solid tumors. Very importantly, the specificity of the T cell for the each tumor needs to be established prior to infusion.
Q: With this level of specificity, could adoptive transfer of specialized T cells become a non-toxic cancer treatment?
A: Yes! For adoptive neoantigen-specific T cell therapy to work efficiently and reliably—and I have no doubt that it will work—we will need to further the technology. We need to find a way of understanding why sometimes T cells kill the peptide and not the tumor, and we absolutely need to industrialize the process, which right now is very cumbersome. But once the principle is proven, the technology will evolve. It is a question only of when. I am certain that adoptive transfer of T cells will become the therapy of choice. Ideally, we should be capable of preparing the patient's cells in vitro for infusion and expand them in vivo by subsequent vaccination.
1 Montagna D, Maccario R, Locatelli F, et al. Ex vivo priming for long-term maintenance of antileukemia human cytotoxic T cells suggests a general procedure for adoptive immunotherapy. Blood. 2001;98(12):3359-3366.