Clinical Study Of Psma
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| First Posted : April 29, 2022Last Update Posted : April 29, 2022 |
We designed a clinical study and divided the trial into two phases.
Phase 1 : 9 patients were randomly divided into 3 groups . 9 patients were treated with cyclophosphamide at the dose of 60mg/kg/d 8-7 days before CAR-T cell infusion, and fludalabine at the dose of 25mg/m^2/d 6-2 days before CAR-T cell infusion. On Day 0, CAR T cells were injected into patients in group 1, 2 and 3 at the dose of 1*10^8/ person, 1*10^9/ person and 1*10^10/ person, respectively. The infusion time exceeded 15-30min. On day 0-14, IL-2 was injected subcutaneously once a day. From day 15-28, IL-2 was subcutaneously injected into the patients three times a week. The purpose of this study is to assess subjects’ MTD against CAR T cells.
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.
Current Prostate Cancer Tumour
TAAs possess an epitope that is specific to cancerous tissue, and weakly expressed or absent on healthy tissue. It does not necessarily need to be target tissue-specific , if the TAA is ubiquitously expressed in cancerous cells. Furthermore, the TAA should lack heterogeneity in expression across tumour cells and be able to constitutively direct an immunological response effecting cell death . With respect to CAR-T therapy, TAAs should also be expressed on the cellular surface. Several TAAs have been investigated within prostate cancer and are outlined in Table 1.
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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 .
More Than Just Car T Cells: Tils And Tcrs
CAR T cells have garnered the lion’s share of attention when it comes to cellular therapies. But other types of cellular therapies have also shown promise in small clinical trials, including in patients with solid tumors.
One type, known as tumor-infiltrating lymphocytes , uses immune cells that have penetrated the environment in and around the tumor. Researchers at NCI were the first to use TILs to successfully treat patients with advanced cancerinitially in melanoma and later in several other cancers, including cervical cancer. More recently, NCI researchers have developed a technique for identifying TILs that recognize cancer cells with mutations specific to that cancer and identifying people whose cancers are more likely to respond to TIL therapy.
The other type of cellular therapy involves engineering patients’ T cells to express a specific T-cell receptor . Unlike CARs, which use portions of synthetic antibodies that can recognize specific antigens only on the surface of cells, TCRs use naturally occurring receptors that can also recognize antigens that are inside tumor cells.
To date, TCR T cells have been tested in patients with a variety of solid tumors, showing promise in melanoma and sarcoma.
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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 .
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.
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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.
New Treatment Options Where Few Existed
The initial development of CAR T-cell therapies focused largely on the most common cancer in children, acute lymphoblastic leukemia .
More than 80% of children diagnosed with ALL that arises in B cells, the predominant type of pediatric ALL, will be cured by intensive chemotherapy. But effective treatments have been limited for patients whose cancers return, or relapse, after chemotherapy or a stem-cell transplant.
In 2017, however, a new option appeared, with FDAs approval of tisagenlecleucel , the first CAR T-cell therapy to be approved by the agency, based on clinical trials demonstrating it could eradicate cancer in children with relapsed ALL.
In some cases, CAR T-cell therapy has now been studied long enough that details about the long-term outcomes in children are beginning to emerge.
An NCI-led research team, for example, recently reported on long-term follow-up from children with relapsed ALL who had been treated with CAR T cells as part of a clinical trial. More than half the children went on to receive a potentially curative stem-cell transplant, they found, and approximately 60% of those children were still alive 5 years later without their cancer coming back or the children experiencing any disease-related problems.
The results in lymphoma to date “have been incredibly successful,” Dr. Kochenderfer said, “and CAR T cells become a frequently used therapy for several types of lymphoma.”
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The Activation And Proliferation Of T Cells
The complete activation of T cells requires the help of dual signal systems and cytokines. First signal comes from the combination of TCR and MHC IAg and the transduction of specific antigen stimulation signals into the cells by CD3. The signal can and enhance the affinity of LFA-1 with inter-cellular adhesion molecule , which plays an important role in prolonging and stabilizing the combination of TCR and MHC I-Ag and the activation of T cells. The second signal is produced by the interaction between T cell membrane and APC membrane surface, mainly between B7 on APC membrane and CD28 on T cell membrane. The double signals activate different signaling pathways and a variety of transcription factors to promote the production of cytokines such as IL-2 that can active T cells fully and make them survive longer.9 The activated T lymphocytes proliferate rapidly, and CD8+ T lymphocytes further differentiate into cytotoxic T lymphocytes that migrate to specific antigen aggregation site for biological effects.
Challenges In Solid Tumours
Whilst CAR-T cell therapy has revolutionised the treatment of haematological malignancies, this success has largely not been repeated in solid tumours. The reasons for this are thought to be due to many factors .
Barriers in CAR-T cell therapy and strategies adopted in overcoming these barriers. Abbreviations: TGF-βâtumour growth factor beta TregsâT regulatory cells MDSCsâmyeloid-derived stem cells M2-MÏâM2 macrophages CAFâcancer-associated fibroblasts PD-1âprogrammed cell death type 1 PD-Lâprogrammed death ligand shRNAâshort hairpin RNA. Created with BioRender.com .
Unlike haematological malignancies, solid tumours express antigenic heterogeneity rather than monoclonality , and therefore some tumours in certain individuals may express a combination of antigens that may differ from another individualâs. Intratumoural heterogeneity is also common in prostate cancer hence, an individual tumour itself may display a wide variety of antigens. Furthermore, there is evidence that CAR-T treatment can induce antigen escape by means of adaptive resistance . Given the low tumour mutational burden and the antigenic heterogeneity, a useful approach is manufacturing CARs that target multiple antigens. Kloss et al. and Feldmann et al. created CARs that target PSCA and PSMA, demonstrating effective results .
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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.
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T Cell Engineering Begins
As a postdoctoral student at the Whitehead Institute at MIT, immunologist Michel Sadelain begins using newly developed genetic engineering tools, specifically retroviral vectors, to introduce genes into T cells, with the goal of making souped-up cancer fighters. This idea would bear fruit in the coming years.
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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 .
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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Diabodies And Bispecific T
Another approach could be to use bispecific antibodies or BITEs . These constructs not only bind to the minimal binding domains of monoclonal antibodies for CD3ϵ T-cell receptor-associated molecule on the T-cell surface, but also to a specific antigen expressed on the surface of cancer cells. Concurrent engagement of both the specific antigen and CD3 leads to tumor cell lysis through the activation of cytotoxic T-cells, regardless of the TCR-mediated specificity of these cells . The relative specificity and sensitivity of BiTE and CAR constructs has been compared in preclinical models . Given that BiTEs may be beneficial in cancers in which a specific epitope is overexpressed compared with normal tissue, as described by Stone et al., this approach has also been studied in PCa.
Several studies developed and evaluated in vitro the efficacy of these novel antibodies in targeting PSCA and PSMA . However, some failed to block cancer cell proliferation in animal models, only delaying tumor growth, suggesting that diabodies used as a single treatment do not achieve a durable cellular memory response . Despite this, administration of the humanized bispecific antibody MOR209/ES414 in murine xenograft models of human PCa led to the inhibition of tumor growth and increased survival, decreasing PSA expression only in adoptively transferred human T cells A phase I study is ongoing to identify the maximum tolerated dose and to test the clinical activity of ES414 in mPCa patients .
Fda Lifts Clinical Hold On Trial Of Car
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The FDA lifted its clinical hold on a study evaluating BPX-601 and rimiducid for patients with previously treated metastatic pancreatic or prostate cancers, according to a press release from the agents manufacturer.
BPX-601 is an autologous chimeric antigen receptor T-cell therapy that targets tumor cells expressing high levels of prostate stem cell antigen .
The investigational therapy uses Bellicums proprietary dual-switch GoCAR-T, which allows clinicians to either activate or eliminate the CAR T cells with the administration of small molecules to enhance real-time control of the agent.
The small molecule being used in the study is rimiducid , an investigational lipid-permeable tacrolimus analogue with homodimerizing activity.
Researchers designed the phase 1/phase 2 dose-escalation trial to evaluate the safety and efficacy of BPX-601 and rimiducid among patients with previously treated advanced solid tumors including pancreatic, stomach or prostate tumors that express high levels of PSCA.
The agency placed the trial on hold in December after the manufacturer reported the death of one participant with pancreatic cancer. The study investigator determined the death to be unrelated to either study drug.
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