Novel Tx Helped Man With Recurrent Brain Tumor – MedPage Today

A 36-year-old man presents to a medical research institute in Los Angeles with neurological symptoms. Clinicians taking the patient's history learn that 4 years previously, he was diagnosed with an astrocytoma identified as isocitrate dehydrogenase (IDH)-mutant diffuse, with a lesion in the right frontoparietal lobe, which was surgically resected.

After the tumor recurred in the same location 6 months later, a second surgery was performed, followed by radiation therapy.

At the time of the patient's current presentation due to neurological symptoms, clinicians order a perfusion MRI, which reveals lesions in the right frontoparietal (2.5 cm) and left parieto-occipital lobes (1 cm).

Two months later, a perfusion identifies subtotal surgical resection of the tumors, and based on the pathology report, the patient is diagnosed with IDH-mutant glioblastoma multiforme (GBM).

For the next month, the patient receives standard treatment with adjuvant chemoradiation therapy with 59.4 Gy/33 fractions radiation and 75 mg/m2 temozolomide.

The patient is enrolled to receive an institutional review board-approved experimental combination immunotherapy. Consistent with FDA regulations for tissue/cell-based treatment practices, the team identifies an inhibitory killer immunoglobulin-like receptor [KIR]-human leukocyte antigen [HLA] KIR-HLA-mismatched haploidentical relative as a cell donor, a protocol based on a previously reported approach for intentionally mismatched natural killer (NK) cells.

This treatment is administered from November 2019 through January 2020. Before initiation of the experimental therapy, the patient receives pre-conditioning with a moderate dose of fludarabine (15 mg/m2/d) on days -7 through -4.

On day -1, a dose of 3 million/m2 IU interferon alpha is subcutaneously injected.

On day 0, 1.6 billion (18 million/kg) allogeneic, highly purified (>95%) IL-2 activated NK cells are administered via intravenous infusion, followed by five daily subcutaneous injections of interleukin (IL)-2 (6 million IU/m2).

Thirty days after receiving the NK cell infusion, the patient receives an intramuscular injection of tetanus-diphtheria (td) vaccine to prime a cellular immune response.

One day later, clinicians start the patient on a 21-day course of a dose-intensified (di)-temozolomide regimen (100 mg/m2).

On day 21 of the cycle, the patient is given a td vaccine, administered intradermally into his right groin area.

On days 22, 29, and 36, the patient receives 5 million viable allogeneic, monocyte-derived dendritic cells pulsed with cytomegalovirus (CMV)-pp65 antigen intradermally into the right groin area.

The case authors explain that throughout the treatment regimen, the patient also receives a cyclooxygenase-2 inhibitor at 200 mg/day, with the aim of limiting the inflammatory symptoms of the immunotherapy and immune tolerance buildup against cancer by controlling regulatory T cells.

He has no grade III or IV adverse events, and on the days he receives the cell therapies, he has mild, self-limited fever along with grade 1 lymphopenia at the end of the di-temozolomide regimens.

At assessments 1 month following NK cell infusion and 1 week after the first dendritic cell injection, contrast-enhanced MRI reveals no evidence of residual tumor. Perfusion MRIs from months 3, 6, 12, and 15 show continued complete response.

Post-immunotherapy follow-up axial T2 fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans of the brain: (A) 3-month, (B) 6-month, (C) 12-month, (D) 15-month contrast-enhanced MRI images with evidence of no tumor recurrence, demonstrating durable complete response.

Discussion

Clinicians presenting this case of a young man with recurrent glioblastoma and residual tumor note that the novel treatment strategy of allogeneic NK cells combined with dendritic cells pulsed with cytomegalovirus-pp65 was associated with durable complete response.

The case authors note that although about 25% of GBM patients receiving temozolomide can survive 2 years, the median overall survival is only 9.5 months, and that outcomes are better among those with no residual tumor after surgery and those who receive long-term temozolomide.

A 2021 review of patients with newly diagnosed glioblastoma found that while the incidence is low compared with other cancers such as lung, breast, prostate, and colon cancers, it dwarfs these other tumor types in terms of average years of life lost -- i.e., 20.1 years for glioblastoma vs 6.1 years for prostate cancer and 11.8 years for lung cancer.

In addition, GBM typically affects patients in the prime of their lives. Thus, the disease represents a very important problem in oncology, with a grim prognosis that has changed little since the 1970s.

A recent evaluation of standard treatment strategies for GBM from two centers in the Netherlands found that after adjustments for confounders, patients with recurrent GBM selected for treatment with re-resection followed by adjuvant treatment or systemic treatment survived 7.3 and 11.0 months -- significantly longer than the 3.1 months noted in patients selected for best supportive care (P<0.001 for both). Survival with re-irradiation was 9.2 months, which was not significantly different for patients selected based on clinical parameters to receive best supportive care (P=0.068).

The case authors note that clinical studies of GBM patients receiving CMV-pp65 antigen-loaded dendritic cell vaccines have reported significant clinical benefits, although those studies involved patients who were already in remission or had minimal residual disease before any recurrence, and treatment used the patients' own dendritic cells.

The case authors referenced six studies of various immunotherapies that led to the hypothesis that informed their experimental treatment combination of allogeneic NK and dendritic cells pulsed with CMV-pp65.

GBMs have been linked with complex immunosuppressive effects within the tumor microenvironment, including secretion of IL-10 and transforming growth factor beta, recruitment of M2-macrophages and regulatory T cells and their upregulation of immune checkpoint ligands and major histocompatibility (MHC) class I receptors on their surface, the case authors note.

And while GBMs have responded to treatment involving adoptive transfer of T cells, studies in mice have shown that NK cells can effectively eliminate GBM, with the added benefit of minimal graft versus host disease in comparison to T cells.

Increased levels of MHC class I molecules on the surface of GBM cells can lead to immune evasion by inhibiting NK cytolytic function; the case authors suggest this might be able to be overcome with allogeneic NK cell transplantation from an MHC class I-mismatched donor.

The team cites studies showing that use of KIR-HLA-mismatched NK cell therapy helps improve elimination of glioma stem cells, and that this approach has also been effective in GBM patient-derived xenograft animal models, and in patients with advanced non-small cell lung cancer.

Dendritic cells provide a direct link from innate immunity to adaptive immune response by digesting and presenting an antigen to the adaptive immune system, the case authors explain, citing a clinical trial in which vaccination with dendritic cells plus concomitant standard therapy was associated with extended survival in GBM patients.

Furthermore, extended survival has been reported in patients vaccinated with autologous dendritic cells who received adjuvant temozolomide, which appears to enhance NK activation. The case authors note that since CNV is expressed in over 90% of GBMs, studies have appeared to link vaccination with CMV-primed dendritic cells with increases in both progression-free survival and overall survival in patients with non-recurrent GBM.

The authors explain that while their use of combination immunotherapy consisting of allogeneic NK and dendritic cells that were intentionally mismatched for inhibitory KIR/HLA reflects existing study protocols and previous reports, this is believed to be the first time the combination of both cell therapies was administered to a GBM patient with residual tumor.

Based on the reported ability of NK to target chemotherapy-resistant cancer cells and GBM stem-like cells, clinicians initiated the combination immunotherapy protocol with use of intentionally mismatched NK cells in order to address and potentially eliminate residual disease.

After the residual disease was addressed, the tumor surveillance elicited by a vaccine-based immunotherapy would have a better potential to control the disease and prevent relapse, the authors said.

And while they acknowledged that individual treatment components i.e., temozolomide, NK cells, or dendritic cells may have generated the complete response, with or without CMV-pp65, existing data along with the fact that this patient achieved complete remission for over a year shows the potential enhanced immunotherapeutic effects of intentionally and strategically mismatched allogeneic cell therapies compared with existing autologous therapy models in clinical development.

This suggests that new immunotherapy strategies are worthy of further study, the case authors stated.

Conclusion

They concluded that their patient with recurrent GBM achieved durable complete remission with a novel treatment strategy with allogeneic NK cells and dendritic cells pulsed with CMV-pp65 despite having residual tumor following surgical resection, and that if the approach is confirmed in additional patients, the approach could offer an effective therapeutic option for people with an otherwise dismal prognosis.

Disclosures

The case report authors noted no conflicts of interest.

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Novel Tx Helped Man With Recurrent Brain Tumor - MedPage Today