Immunotherapy Trial Gives Renewed Hope To Patients With Incurable Prostate Cancer
Six years ago, Charlotte resident Rodney Glover retired from Atrium Health. He had enjoyed over 30 years of incredibly fulfilling work in the heart catheterization lab, where he helped stop heart attacks in their tracks.
Just before his retirement, he started having some concerning urinary symptoms. His internist ordered a biopsy and later diagnosed him with prostate cancer. At the time, Rodney thought, You die with prostate cancer, not from prostate cancer.
Rodney was later referred to Dr. Earle Burgess, chief of Atrium Health Levine Cancer Institutes genitourinary oncology program and medical director of the clinical trials unit. Rodneys scans showed metastatic prostate cancer that had spread to his bones.
He initially responded well to chemotherapy, but then his prostate-specific antigen levels began to rise. They continued to increase on a steady incline, which meant he needed more treatment.
Burgess told Rodney about a new study involving chimeric antigen receptor T-cell therapy. For over five years, this revolutionary therapy has been helping patients with blood cancers, curing many who would otherwise have died. Researchers are now trying to apply the treatment to patients with metastatic solid-state tumors, like prostate cancer.
CAR T-cell therapy is a personalized treatment thats made by removing T lymphocytes from the patient and engineering them to be able to recognize and attack the patients own cancer cells.
Translating Our Successes With Car T Cell Therapy Toward Solid Tumor Cancers
- Weve treated over 630 patients in nearly 80 CAR T cell trials , targeting both solid and liquid tumors.
- We were one of the first to spearhead CAR T cell therapy as a potential bridge therapy to BMT for patients with leukemia and lymphoma.
- Weve received several multimillion-dollar grants to explore CAR T cell therapies in multiple hematologic and solid tumors, including leukemia, multiple myeloma, lymphoma, glioblastoma, prostate and HER2-positive breast cancer with metastatic brain disease.
- We developed a , highly specific chlorotoxin CAR T cell therapy to treat glioblastoma
- City of Hope has licensed the CAR T cell therapy to Chimeric Therapeutics Limited, an Australian biotechnology company who will further develop the therapy for other cancers and extend the treatment to more patients.
Epithelial Cell Adhesion Molecules
EpCAM, also known as CD326, is a stem cell antigen expressed by several solid tumors, including PCa . An EpCAM-CD3 bispecific antibody was recently approved in Europe for patients with malignant ascites. Using this molecule as a TAA, Deng et al. developed EpCAM-specific CARs which not only proved capable of killing PC3M prostate cells but also of prolonging survival in PC3 prostate cells . Further investigation is warranted into the role of this molecule in mPCa .
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Car T Cells Reach Clinical Milestone In Prostate Cancer
volume 28, pages 635636
Armored CAR T cells show early signs of clinical activity in patients with castration-resistant prostate cancer, paving the way for further development and optimization.
Cancer progression is often fueled by a preponderance of genetic aberrations such as mutations, amplifications and divergently expressed genes. These can lead to newly expressed peptides that are entirely absent from normal human tissues, or to peptides that are expressed at higher levels in tumors, but are also expressed at lower levels in other tissues the latter are known as tumor-associated antigens.
Leading Cellular Therapy Program
Levine Cancer Institute was selected among the limited number of sites for this study because it offers one of the nations leading cellular therapy programs. It is also known for its comprehensive transplant program, exceptional research and reputable genitourinary oncology program. Burgess added, We also have a notable track record and a high volume of experience with CAR-T trials.
LCI has disease-specific experts who specialize in treating patients with one type of cancer. For example, Burgess only treats patients with prostate and related cancers in the genitourinary tract. This allows him to provide the most effective, personalized treatments based on his patients unique needs.
Our goal is to continue to have access to cutting-edge technologies, including CAR T-cellular therapy trials, Burgess explained. Were hoping this treatment proves to be effective in patients so we can do even more with potential breakthrough therapies in the future.
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Asco 202: Car T For Prostate Cancer: Current Strategies To Improve Efficacy
In her portion of this case-based panel, Dr. Dorff described chimeric antigen receptor T-cell therapy and its potential use in prostate cancer. She indicated that CAR-Ts are especially exciting given their potential to induce long-term disease responses, such as have been seen in leukemias and lymphomas. CAR-T cells are a flexible platform, where in addition to introducing a chimeric receptor against a tumor antigen into T-cells, they can be engineered to have immune-co-stimulatory domains and even secrete cytokines to help support T-cell proliferation. Future generations of CARs may also have a conditional expression or be able to be targeted against multiple tumor antigens.
After this introduction, Dr. Dorff focused her discussion on two clinical trials of CAR-T therapy in prostate cancer that have already read-out initial data. The first is a trial of the Poseida P-PSMA 101 therapy, which was initially presented at ASCO GU 2022. The features of this therapy are shown in the slide below, and include selection for a more-stem cell like T-cell population in case this allows for longer cell survival, and a Cas9 based safety switch.
One potential side effect of CAR-T therapy is an immune syndrome similar to macrophage activation syndrome/hemophagocytic lymphohistiocytosis. This is characterized by fever and elevated inflammatory markers, and can be managed with multiple agents such as steroids, ocilizumab or anakinra.
The Molecular Structure Of Car
The CARs are fusion proteins constructed by modern molecular biotechnology. CARs are generally composed of three parts: extracellular antigen identification zone, transmembrane zone, and intracellular signal transduction zone.5 The extracellular antigen identification zone is the basis of specific recognition of tumor antigens by CARs.6 Single-chain fragment variable of CAR-T cells can recognize tumor-associated antigen specifically. The transmembrane zone usually consists of the transmembrane region of CD3, CD8, CD28, or FcRI and can fix scFv on the surface of T cells and transduce the signal into the cells. The intracellular signal transduction zone is composed of CD8, CD28, or CD137 intracellular area and CD3, which contain the immune-receptor tyrosine-based activation motif . ITAM plays a crucial role in the transduction of signal to active T cells.
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G And 3g Car T Cells Show Comparable Tumor Cell Killing And Cytokine Production Following Exposure To Psma+ Cells
Both the 2G and 3G CAR populations lysed the PSMA-transfected PC3 cells at high levels . Moreover, they efficiently recognized LNCaP cells, a target that naturally harbors the PSMA antigen , while sparing the antigen-negative counterpart . Other than exerting a relevant cytotoxic activity, both generations of CAR-transduced T cells also produced high and comparable levels of IFN-, IL-2, and TNF- in response to PSMA-expressing tumor targets, but not against PSMA negative control cells .
Figure 3 Functional characterization of the 2G and 3G CAR-expressing populations. Lytic activity of the 2G and 3G -CAR expressing populations. Cytotoxicity was analyzed at day 15 post-transduction as target cells, PC3-PSMA, LNCaP, and PC3 were used. Cytokine release upon antigen stimulation. IFN-, IL-2 and TNF-. Cytokine release was evaluated 15 days after T cell infection by stimulating 2G and 3G CAR populations with PC3-PSMA or PC3 cancer cell lines. Negative and positive controls were represented by 2G and 3G CAR T cells treated or not with PMA/Ionomycin. Figures show the mean +/- SD of 3 independent experiments.
Making The Car T Cells
After the white cells are removed, the T cells are separated, sent to the lab, and altered by adding the gene for the specific chimeric antigen receptor . This makes them CAR T cells. These cells are then grown and multiplied in the lab. It can take several weeks to make the large number of CAR T cells needed for this therapy.
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Alleviating Immunosuppression To Enhance Car T
Posted January 29, 2021 Saul Priceman, Ph.D., City of Hope Medical Center
In recent years, the idea of using ones own immune system to fight off cancer has blossomed into a promising therapeutic strategy. T-cells, which are white blood cells that can recognize and kill other cells, can be harvested from patients and engineered to target their specific cancer. These modified Chimeric Antigen Receptor T-cells are then introduced back into the patient to hunt and destroy cancer cells. This process known as Adoptive T-Cell therapy, has been used to effectively treat different blood cancers. However, it has not been successful with prostate cancer as the tumor can hijack the local immune environment to block and evade treatment.
Dr. Saul Priceman and his team at the City of Hope Medical Center have been working on developing a therapy that can overcome immunosuppression so CAR T-cells can recognize and target prostate cancer cells in the body. With the support of a FY16 Idea Development Award he identified that a cyclophosphamide treatment can deplete the immunosuppressive environment that surrounds prostate tumors. This is combined with T-cells that are engineered to recognize Prostate Stem Cell Antigen , a protein that is highly expressed on the cell surface of prostate cancers.
Figure 1. Treatment with cyclophosphamide significantly increases survival of mice treated with PSCA targeting mouse CAR T-Cells .
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Research Award Accelerates Research On Car T
According to the American Cancer Society, one in eight men will receive a prostate cancer diagnosis in his lifetime and about one in 40 will die as a result. A Keck Medicine of USC research team has now developed an innovative treatment for prostate cancer, known as synthetic immune receptor T-cell therapy. The new technology was adapted from chimeric antigen receptor therapy, which has been proven effective for several types of blood cancer.
Principal investigator Preet M. Chaudhary, MD, PhD, chief of the Jane Anne Nohl Division of Hematology and Center for Blood Diseases in the Department of Medicine, Bloom Family Chair in Lymphoma Research and director of Blood and Marrow Transplant and Cell Therapy at the Keck School, has been selected to receive a $5.8 million award from the California Institute for Regenerative Medicine to begin conducting preclinical studies of SIR-T therapy.
To continue reading this story, .
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Prostate Taas And Known Immunotherapy Strategies
The identification of prostate TAAs is the first step towards developing an effective CAR-T cell therapy. An ideal antigen should be constitutive and specifically expressed by cancer cells to enable CAR-T cells to develop a cancer-specific immunologic response, thus sparing healthy tissue . In PCa the group of protein preferentially expressed by malignant cells are prostate-specific antigen , prostatic acid phosphatase , prostate stem cell antigen , T-cell receptor gamma alternate reading frame protein , transient receptor potential -p8 and prostate-specific membrane antigen . In recent years, several studies have used prostate TAAs as a target for the induction of an immunological response in PCa patients .
Pros and Cons of using each TAA in the development of CAR-T cells in prostate cancer
More Target Antigens Including For Solid Tumors
Research on CAR T cells is continuing at a swift pace, including hundreds of ongoing clinical trials. Part of this expansion is a product of researchers having identified additional antigens on tumor cells that might be good targets for CAR T cells.
Although CD19 and BCMA are the only antigens for which there are FDA-approved CAR T-cell therapies, CAR T-cell therapies have been developed that target other antigens commonly found in blood cancers, including therapies that target multiple antigens at one time.
But what about the use of CAR T cells to treat solid tumors, like brain, breast, or kidney cancer? There, advances have been hard to come by. Efforts to identify antigens that are on the surface of solid tumors but not healthy cells, Dr. Rosenberg said, have largely been unsuccessful.
Another obstacle with solid tumors is their surrounding environment. Physical barriers, for example, can prevent the infused CAR T cells from reaching tumor cells. Other components of the microenvironment, such as immune-suppressing molecules produced by tumor cells or other immune cells, can cause CAR T cells to malfunction, leaving them unable to carry out their cell-killing duties.
Perhaps the biggest barrier is an age-old problem: tumor heterogeneity, said Crystal Mackall, M.D., director of the Parker Institute for Cancer Immunotherapy at Stanford University.
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Prostate Stem Cell Antigen
PSCA is a cell membrane glycoprotein that is expressed by prostate cells. Expression rates of PSCA in prostate cancer tissue are almost 90% higher than in benign tissue . Additionally, a positive correlation exists with PSCA expression and advanced clinical disease. Gu and colleagues examined 120 primary prostate cancer and metastatic specimens and found that the level of PSCA expression was associated with higher Gleason score, higher tumour stage and androgen independence . Furthermore, 100% of the metastatic specimens examined demonstrated expression of PSCA. PSCA is also exclusively expressed on the cell surface and not released into the blood . Hence, the biological features of PSCA are favourable for immunological targeting. PSCA has been investigated as a potential target for antibody-based immunotherapy.
Morgenroth et al. first developed anti-PSCA CAR-T cells in 2007 and were able to demonstrate effective lysis of PSCA-expressing cells . Since then, several preclinical models have been evaluated with PSCA-specific CAR-T cells. A limiting factor of in vitro testing is that there are no prostate cancer cell lines that endogenously and uniformly express PSCA culture conditions. As such, these cell lines are either transfected or transduced to express PSCA. PSCA-CAR-T cells have demonstrated specific and effective cytokine release as well as cell lysis in vitro against a variety of cell lines that have been genetically transduced to express PSCA .
Collecting The T Cells
First, white blood cells are removed from the patients blood using a procedure called leukapheresis. During this procedure, patients usually lie in bed or sit in a reclining chair. Two IV lines are needed because blood is removed through one line, the white blood cells are separated out, and then the blood is put back into the body through the other line. Sometimes a special type of IV line called a central venous catheter is used, which has both IV lines built in.
The patient will need to stay seated or lying down for 2 to 3 hours during the procedure. Sometimes blood calcium levels can drop during leukapheresis, which can cause numbness and tingling or muscle spasms. This can be treated by replacing the calcium, which may be given by mouth or through an IV.
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G And 3g Car T Cells Exhibit A Similar Trend In The Accumulation Of The Car
To generate T cells expressing 2G or 3G CAR anti-PSMA, we used a previously described expansion protocol that involved weekly restimulations with PC3-PSMA cells. Thus, both CAR T cell populations had the chance to encounter the antigen, which sustained the expansion of the CAR-expressing subset . To characterize the state of differentiation of CAR-transduced T lymphocytes in the post-infection period and during antigenic restimulation, we cytometrically analyzed the expression of different surface markers, namely CD62L, CD27, CD28, CCR7, and CD57. One week after transduction, 2G CAR T cells presented the typical characteristics of early effector T cells, as shown by the high expression of CD62L , the presence of CCR7 , CD27 and CD28 , and the low expression of CD57 . Conversely, 3G CAR T cells showed a significant difference in the expression of CD62L and CCR7 already at the first week post-transduction, and very rapidly acquired a more differentiated effector memory phenotype. Following re-stimulation with the antigen, both T cell populations down-modulated CD62L, CCR7, CD28 and presented a slight increase in CD57 expression, thus progressively acquiring an intermediate effector memory phenotype. Moreover, we observed that T cells are mostly stem cell memory 3 days after transduction, to progressively switch into T central memory and T effector memory after 15 and 25 days, respectively .
Construction Of A Second
The 2G and 3G CAR sequences were inserted into a Lentiviral Vector carrying a minCMVPGK bidirectional promoter that allows the simultaneous and coordinated expression of two genes, a reporter gene and the anti-PSMA CAR . The 2G and 3G CAR sequences were designed that encoded the following components: the single-chain variable fragment of the anti-PSMA antibody IgGD2B , a myc tag for cytofluorimetric detection, and the CD28 co-stimulatory molecule linked directly to the CD3 sequence, for the 2G CAR the 3G CAR presented a second co-stimulatory molecule within the CD28 and CD3 domains . The anti-PSMA scFv used for the development of CAR structures is well described , and presents very promising characteristics, especially the high affinity for the target. T cells were transduced with LV 2G and 3G CAR PSMA/eGFP. One month after transduction, more than 90% of cells were CAR+ , with a balanced expression of both the CAR and the reporter gene sustained by the bidirectional LV .
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Are There Any Other Ongoing Trials Assessing The Use Car T
Multiple trials are open and accruing. We have 3 of them open here at City of Hope, 1 with our own PSCA-targeted CAR T-cell product. Were just finishing up phase 1 study and expect to open the phase 1b study later this summer where were going to be testing multiple dosing and radiation prior to CAR T-cell administration, which in the lab seems to augment responsiveness a good number of patients already have been treated. The PSMA targeted CAR T from POSEIDA is still accruing. Weve treated 7 here. Its a multi-site study, so there are many other sites that have treated patients as well, and thats still ongoing. Then there’s the KLK2 targeted CAR T-cell study from Janssen. Thats a little earlier along but theyve treated a fair number of patients at this point its a multicenter study. This is already a reality in terms of clinical trials, but still far from practice.