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PubMed2026

Predictive Biomarkers for Immune Checkpoint Inhibitor Efficacy: Challenges, Innovations, and a Pathway to Precision Medicine in the Era of Cancer Immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed oncology practice. However, treatment response remains heterogeneous, rendering predictive biomarkers critical for optimal patient care. The 3 established biomarkers, programmed death-ligand 1, tumor mutational burden (TMB), and microsatellite instability-high/deficient mismatch repair, are approved and clinically validated but are modest predictors of benefit. As a result, multiple novel predictive biomarkers remain under investigation. CONTENT: This review highlights established and investigational predictive ICI efficacy biomarkers. For established biomarkers, we describe biology, assay modalities, approved companion diagnostics, landmark studies, and notable limitations. Due to the multisystem nature of antitumor immune effects, investigational biomarkers span multiple domains, including tumor genomic biomarkers (e.g., mutational signatures, TMB, neoantigen clonality), tumor microenvironment (e.g., tumor-infiltrating lymphocytes [TILs], tertiary lymphoid structures), systemic immune biomarkers (e.g., cytokines, autoantibodies, glycoproteins, peripheral blood mononuclear cells), and the microbiome (e.g., gastrointestinal microbial diversity, responder-enriched taxa). SUMMARY: The established biomarkers PD-L1, TMB, and microsatellite instability-high/deficient mismatch repair inform ICI use in clinical practice but have important limitations. Multiple investigational biomarkers show promise in refining patient selection and optimizing therapy. Moving forward, increased assay harmonization, prospective validation, and standardized parameters may improve performance. Composite models integrating complementary signals across domains may further individualize treatment and lead to an era of personalized cancer immunotherapy.

Humans↗
PubMed2000

A herpesvirus saimiri-based gene therapy vector with potential for use in cancer immunotherapy.

The herpesvirus saimiri (HVS) genome has the capacity to incorporate large amounts of heterologous DNA and can be maintained episomally in many different human cell types. To evaluate the efficacy of HVS-mediated gene transfer into human hemopoietic cells, we investigated the ability of an HVS-based construct, carrying the enhanced green fluorescent protein (EGFP) and neomycin resistance genes, to transduce a variety of human hemopoietic cell lines and primary CD34+ cells. As measured by flow cytometry, the numbers of EGFP+ cells at 2 days postinfection differed between various cell types ranging, from 1.3% for KG1 cells to 56.8% for THP-1 cells. In addition, the expression of EGFP in Jurkat cells was retained at >95% per round of cell division over a period of 6 weeks (comparable with Epstein-Barr virus-derived gene therapy systems). Although the virus was not specifically disabled, no lytic viral mRNAs could be detected in transduced Jurkat cells, and infectious virus could not be detected by sensitive virus recovery assay. We also describe a simple centrifugation method that increases the efficiency of transduction by >100% in some cases and may be generally applicable to other herpesvirus-based vectors for ex vivo gene delivery. Using this technique, we were able to demonstrate a tropism for CD34+/CD14+ cells, transducing 30% of the population. These cells are known to give rise to dendritic cells (the most potent of the antigen-presenting cells), suggesting that the vector could be used to deliver DNA sequences encoding tumor antigens for cancer immunotherapy.

Antigens, CD34↗
PubMed2005

Natural killer-dendritic cell cross-talk in cancer immunotherapy.

Natural killer (NK) cells and dendritic cells (DCs), two important components of the immune system, can exchange bidirectional activating signals in a positive feedback. Myeloid DCs, the cell type specialised in the presentation of antigen and initiation of antigen-specific immune responses, have recently been documented to be involved in supporting innate immunity, promoting the production of cytokines and cytotoxicity of NK cells, and enhancing their tumouricidal activity. Natural interferon-producing cells/plasmacytoid DCs (IPCs/PDCs) play an additional role in NK cell activation. Reciprocally, NK cells, traditionally considered to be major innate effector cells, have also recently been shown to play immunoregulatory 'helper' functions, being able to activate DCs and to enhance their ability to produce pro-inflammatory cytokines, and to stimulate T helper (Th) 1 and cytotoxic T lymphocyte (CTL) responses of tumour-specific CD4+ and CD8+ T cells. Activated NK cells induce the maturation of myeloid DCs into stable type-1 polarised DCs (DC1), characterised by up to a 100-fold enhanced ability to produce IL-12p70 in response to subsequent interaction with Th cells. In addition, the ability of NK cells to kill tumour cells may facilitate the generation of tumour-related antigenic material, further accelerating the induction of tumour-specific immunity. DC1, induced by NK cells or by NK cell-related soluble factors, are stable, resistant to tumour-related suppressive factors, and demonstrate a strongly enhanced ability to induce Th1 and CTL responses in human in vitro and mouse in vivo models. Compared with the standard mature DCs that are used in clinical trials at present, human NK cell-induced DC1s act as superior inducers of anticancer CTL responses during in vitro sensitisation. This provides a strong rationale for the combined use of NK cells and DCs in the immunotherapy of patients with cancer and patients with chronic infections that are resistant to standard forms of treatment. Stage I/II clinical trials that are being implemented at present should allow evaluation of the immunological and clinical efficacy of combined NK-DC therapy of melanoma and other cancers.

Animals↗
PubMedDate not supplied

Crescentic glomerulonephritis associated with renal cell carcinoma after cancer immunotherapy.

A 59 year-old woman showed rapidly progressive glomerulonephritis during immunotherapy for metastatic renal cell carcinoma. She received unilateral nephrectomy and cytotoxic T lymphocyte (CTL) therapy for the treatment of retroperitoneal lymph node metastasis of renal cell carcinoma. With CTL therapy, her retroperitoneal lymph node mass decreased in size. One year after the third round of CTL therapy, her serum creatinine was increased and massive proteinuria occurred. Her renal biopsy specimen revealed necrotizing and crescentic glomerulonephritis with immune complex deposition. Her retroperitoneal lymph node mass continued to decrease in size. Consequently, for the purpose of avoiding interfering with the CTL therapy, we performed double filtration plasmapheresis (DFPP) monotherapy for removal of immune complexes without using immunosuppressive drugs or prednisolone. After 24 sessions of DFPP, her serum IgG was reduced from 3,942 mg/dL to 2,400 mg/dL, and proteinuria (from 9.0 g/day to 0.9 g/day) and renal function (serum creatinine; from 5.6 mg/dL to 2.2 mg/dL) also improved. However, 3 months after the final DFPP, she expired due to perforation of the colon. The autopsy sample of the kidney showed that most of the glomeruli were obsolescent, but immunoglobulin depositions were reduced and necrotizing lesions were diminished. In the patients with RPGN associated with renal cell carcinoma, renal functional recovery has not been observed upon immunosuppressive treatment. Consequently, plasmapheresis is considered to be one of the effective and safe methods for patients with this association. We also discuss previous reports of RPGN associated with renal cell carcinoma, or RPGN after cancer immunotherapy.

Biopsy↗
PubMed1995

[Tumor rejection antigen and cancer immunotherapy].

Tumor rejection antigen (TRA) recognized by cytotoxic T cells (CTL) have been identified on several murine tumors and human malignant melanomas. By utilizing those peptides as tumor vaccine, a new immunotherapy will be anticipated. Cancer cell vaccine and adoptive transfer of CTL/TIL have been undertaken successfully. Moreover, recombinant protein of tumor rejection antigen and heat shock protein emerge as promissing molecules as tumor antigen. To augument rather weak immune response, cytokine and gene therapies have now begun to be done. Cytokines can be used by themselves and also genes of cytokines can be introduced into either tumor cells or CTL/TIL.

Animals↗
PubMed1999

Target antigens for prostate cancer immunotherapy.

The detection and treatment of prostate cancer has been markedly improved by the use of Prostate-Specific Antigen (PSA) as a serological biomarker for disease. However, even after surgical intervention and hormone ablation therapy, a significant proportion of patients progress to advanced metastatic disease, for which there is no cure. An important goal has become the identification of antigens in advanced stage prostate cancer that represent targets for therapy. Recently, great progress has been made to utilize immunological therapies to treat cancer. Monoclonal antibody therapy has been successfully approved for the treatment of breast cancer and B-cell lymphoma, and multiple clinical trails are currently in progress in a variety of cancers, including prostate cancer. Pre-clinical and clinical studies are also underway to evaluate cancer vaccine approaches directed against antigens that are highly expressed in prostate and other cancers. This article describes several target antigens expressed in prostate cancer and immunological approaches directed against them that may be effective for treating prostate cancer patients.

Acid Phosphatase↗
PubMed2000

An overview of cancer immunotherapy.

The survival of patients with cancer has improved steadily but incrementally over the last century, with the advent of effective anticancer treatments such as chemotherapy and radiotherapy. However, the majority of patients with metastatic disease will not be cured by these measures and will eventually die of their disease. New and more effective methods of treating these patients are required urgently. The immune system is a potent force for rejecting transplanted organs or microbial pathogens, but effective spontaneous immunologically induced cancer remissions are very rare. In recent years, much has been discovered about the mechanisms by which the immune system recognizes and responds to cancers. The specific antigens involved have now been defined in many cases. Improved adjuvants are available. Means by which cancer cells overcome immunological attack can be exploited and overcome. Most importantly, the immunological control mechanisms responsible for initiating and maintaining an effective immune response are now much better understood. It is now possible to manipulate immunological effector cells or antigen-presenting cells ex vivo in order to induce an effective antitumour response. At the same time, it is possible to recruit other aspects of the immune system, both specific (e.g. antibody responses) and innate (natural killer cells and granulocytes).

Adjuvants, Immunologic↗
PubMed1987

Immunotherapy using the streptococcal preparation OK-432 for the treatment of uterine cervical cancer. Cervical Cancer Immunotherapy Study Group.

The effectiveness of immunotherapy using a streptococcal preparation, OK-432, was evaluated for cervical cancer. The 382 eligible patients were stratified by presence/absence of surgical operation and clinical stage, and then, in each stratum, were randomly divided into two groups: an OK-432 treatment group and a control treatment group. The 3-year recurrence-free rates of 221 patients in the OK-432 group and 161 patients in the control group were 71.9% and 58.6%, respectively. The intergroup difference was statistically significant (P less than 0.05). Delayed skin reactions to phytohemagglutinin (PHA) and Su-polysaccharide extracted from Streptococcus pyogenes Su-strain (Su-PS) and peripheral lymphocyte counts were reduced within two months after the initiation of therapy in both groups. The observed immunological changes were apparently reversed by 3 months after the start of the therapy in the OK-432 group, but this took at least one year in the control group, with significant intergroup differences at 6 and 12 months of the therapy (P less than 0.01). These results indicate that OK-432 can be considered as one of the most effective and useful immunotherapeutic agents for cervical cancer.

Biological Products↗
PubMed2004

Identification of antigenic epitopes recognized by Mac-2 binding protein-specific cytotoxic T lymphocytes for use in cancer immunotherapy.

We have previously reported that 90K/Mac-2 binding protein (M2BP) was highly expressed in lung cancer and that M2BP-specific immunity was observed in many of cancer patients. In this study, we analyzed the ability of 11 M2BP-derived oligopeptides with an HLA-A*0201-binding motif to induce M2BP-specific cytotoxic T lymphocytes (CTL) from peripheral blood lymphocytes of normal donors by in vitro stimulation. One of the CTLs that were induced using M2BP216-224 (RIDITLSSV) produced interferon-gamma in response to HLA-A2-positive T2 cells pulsed with the same peptide and lysed MDA-MB-231 cells expressing both M2BP and HLA-A2. The cytolytic activities were blocked by antibodies against HLA class I or CD8. These findings suggest that M2BP216-224 is naturally processed from the native M2BP in cancer cells and recognized by M2BP-specific CTLs in an HLA-A2 restriction. We first identified M2BP-derived CTL epitopes that may be useful as a target antigenic epitope in clinical immunotherapy of cancer.

Amino Acid Sequence↗
PubMed2003

The use of dendritic cells in cancer immunotherapy.

A novel approach to vaccination against cancer is to exploit dendritic cells (DCs) as "nature's adjuvants" and actively immunize cancer patients with a sample of their own DCs primed with tumor antigens. DC vaccination is, however, still at an early stage, slowed in part by the need to carry out research in humans. Nevertheless, valuable proofs of concept have been obtained with respect to the capacity of DCs to expand cancer-directed immune responses. The methods for preparing DCs are being improved continuously, and there are many opportunities to improve efficacy at the level of DC biology. An increased number of Phase I, II and III studies will drive this new area of human research.

Animals↗
PubMed1989

Immunotherapy using the streptococcal preparation OK-432 for the treatment of uterine cervical cancer. Cervical Cancer Immunotherapy Study Group.

The efficacy of immunotherapy using a streptococcal preparation, OK-432, was evaluated in each clinical stage of uterine cervical cancer. The 382 eligible patients were stratified by clinical stage and presence/absence of surgery. Within each stratum, patient's were randomly allocated to OK-432 treatment or to control treatment. OK-432 significantly inhibited recurrence in patients with stage II cervical cancer; the recurrence-free interval and survival time were remarkably prolonged in patients with stage II disease who underwent surgery. However, OK-432 did not significantly prolong these parameters in patients with stage III disease. Retrospective analyses revealed that in patients with or without lymph node metastases who underwent surgery, the recurrence-free interval and survival time were significantly prolonged by OK-432 treatment. These results indicate that OK-432 is an effective and useful postoperative immunotherapeutic agent for uterine cervical cancer.

Biological Products↗
PubMed1994

Bone marrow activation by immobilized antibodies against tumor cells and immunocytes as a potential cancer immunotherapy.

This study was aimed at combining the limited expression pattern of the type 1 mucin glycoproteins on tumors derived from glandular epithelia with the presence of integrin adhesion receptors on hematopoietic cells in order to develop an immunotherapy against certain types of carcinomas. To this end, monoclonal antibodies that recognize molecules on the surfaces of either tumor cells or immunocytes were immobilized on latex beads; proliferation of bone marrow cells, representing a source of preterminally differentiated immunocytes with potential antitumor activity, was measured and compared with that of mature lymphocytes in the presence of beads and irradiated tumor cells. It was found that only beads carrying antibodies against both mucins and leukocyte integrins were capable of inducing proliferation of bone marrow cells while none specifically stimulated mature lymphocytes. A proposal is put forth for the development of tumor-induced proliferation of bone marrow cells as a potential effective immunotherapy for some forms of cancer.

Antibodies, Monoclonal↗
PubMed2003

Tumor antigen-specific T cells and cancer immunotherapy: current issues and future prospects.

The critical role of antigen-specific T cells in the eradication of cancer has been demonstrated in numerous animal models. Data compiled from both in vitro systems and human clinical trials indicate that T cells can be identified that recognize antigenic fragments derived from gene products expressed by tumors. Nonetheless, results from clinical trials have been for the most part disappointing, since vaccine protocols designed to elicit anti-tumor T cell activity have, in the majority of cases, failed to result in tumor eradication and enhanced patient survival. The focus of this review article is to summarize the current status of antigen-specific tumor immunotherapy and provide insight into potential future strategies for the successful activation of T cells for the immunotherapy of cancer.

Animals↗
PubMed2004

Targeting melanoma inhibitor of apoptosis protein with cancer immunotherapy.

Aberrantly expressed or mutated proteins in cancer cells evoke immune recognition, but host reactions are usually insufficient to prevent disease progression. Vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) augments host immunity through improved tumor antigen presentation by recruited dendritic cells and macrophages. By analyzing the immune response of a metastatic melanoma patient who achieved a long-term response to vaccination, we identified melanoma inhibitor of apoptosis protein (ML-IAP) as a target for immune-mediated tumor destruction. Vaccination stimulated a coordinated cellular and humoral reaction to ML-IAP that was associated with extensive tumor necrosis, whereas lethal disease progression was linked with the loss of ML-IAP expression and the absence of intra-tumoral lymphocyte infiltrates. These findings demonstrate that ML-IAP can serve as a tumor rejection antigen, although additional vaccine targets will be required to circumvent immune escape and tumor heterogeneity.

Apoptosis↗
PubMed2003

Cancer immunotherapy: an embarrassment of riches?

There is clear evidence that certain forms of immunotherapy can be successful against certain cancers. However, it would appear that cancerous cells of various origin are exceptionally adept at subverting the immune response. Consequently, it is probable that the most efficacious therapy will be one in which multiple responses of the immune system are activated. There is currently an embarrassment of riches with regard to multiple vaccine strategies in the clinic, although no single method seems to hold the solution. Here, we draw together several of the humoral- and cellular-activating strategies currently under clinical investigation.

Antigens, Neoplasm↗
PubMed2001

[Cancer immunotherapy. A future therapeutical choice?].

The idea that there might be an immune response to cancer has been around for many years. Immunotherapy has a long history, but is only rarely considered as the treatment of choice. Immunotherapy has encountered a number of intrinsic difficulties in cancer, such as the antigenic resemblance between the tumour and normal cells, the rapid kinetic proliferation of tumour cells and their reduced immunogenicity. There are various types of immunotherapy. Aspecific immunotherapy augments the body s immune response without targeting specific tumoral antigens. In adoptive immunotherapy, cells are administered with antitumoral reactivity to mediate neoplasm regression. Specific active immunotherapy is based on the principle that neoplasm cells contain immunogenic sites against which an antitumoral immune response can be induced in an attempt to stimulate the immune system to target specific tumoral antigens. Vaccines against cancer cells are based on a more precise identification of the tumoral antigen components. Passive immunotherapy was limited by the difficulty of obtaining high titering and specificity in early attempts using polyclonal antisera; monoclonal antibodies are currently used alone or in association with radioactive substances and cytotoxic agents. Enormous progress has been made this century in the use of immunotherapy for cancer treatment. It seems likely that the next century will see its increased afficacy, making it one of the possible therapeutic options.

Antibodies, Monoclonal↗
PubMed1991

Acute renal failure with preserved renal plasma flow induced by cancer immunotherapy.

Adoptive immunotherapy in patients with advanced cancer produces significant regression of metastatic disease in selected patients, but it is complicated by severe side effects. Prevention of these complications is still limited because their precise mechanisms remain unknown. For this reason we have investigated renal function and hemodynamic parameters in 16 patients with renal cell carcinoma before and during treatment with a combination of high doses of both recombinant interleukin-2 (rIL2) and recombinant alpha-interferon. After patients had received three injections of combined immunotherapy, there was a decrease in mean blood pressure (-20%), glomerular filtration rate (-25%), urine output (-50%), and fractional sodium excretion (-0.8%). This was associated with an increase in heart rate (+30%), plasma creatinine level (+30%), fractional potassium excretion (+14%) and microalbuminuria (+130%). However, renal plasma flow remained constant. The increment in microalbuminuria may reflect an alteration of glomerular capillary permeability. The reduction in GFR may be accounted either for a decrease in efferent to afferent arteriolar resistance ratio, leading to a decrease in glomerular capillary pressure, or for a decrease in ultrafiltration coefficient, or both. Nonsteroidal antiinflammatory drugs, such as ketoprofen, used to minimize side effects, could considerably worsen renal function and should be avoided in patients treated by rIL2. Our results bring new insights into the pathogenesis of functional acute renal failure and provide a rational basis for the use of vasopressors in the treatment of cytokine-induced acute renal failure.

Acute Kidney Injury↗