ABSTRACT
Background & Aim: Despite the successful implementation of vaccines worldwide, COVID-19 remains a risk in patients with a compromised immune system. Emerging viral variants have also reduced the effectiveness of monoclonal antibody therapies in these patients. New treatment options are therefore required to improve clinical outcomes. Methods, Results & Conclusion(s): T cell immunotherapy has proven effective for the treatment of a number of refractory viral diseases in patients with a compromised immune system. We have now completed the manufacture of a bank of SARS-CoV-2 specific T cells and commenced an open-label phase I clinical trial at the Royal Brisbane and Women's Hospital, Australia. Patients enrolled in the study receive two doses of partially HLA-matched allogeneic T cells at a fortnightly interval. We have thus far recruited and treated three immune compromised patients with SARS-CoV-2 T cells. In two of the three patients treated thus far, the administration of T cell therapy was coincident with the clearance of viral load after 28 days. Viral clearance in these patients was also associated with an increase in circulating SARS-CoV-2 specific T cells. Our preliminary observations suggest that SARS-CoV-2 specific T cell therapy is well tolerated and has the potential to impact viral control in immune compromised patients.Copyright © 2023 International Society for Cell & Gene Therapy
ABSTRACT
Background: Adults and childrenwith cancer are susceptible to severe SARS-CoV-2 disease. Vaccination is protective;data beyond initial response and regarding effect of booster doses are lacking in cancer patients. Method(s): The SerOzNET study assesses SARS-CoV-2 vaccine response in haematological and solid cancer patients aged 5 and older. Patients are recruited pre dose 1 and receive standard BNT162b2 (Pfizer) or ChadOx1-S (AstraZeneca) vaccine. Blood is taken at baseline and after each dose. Neutralizing antibody (NAb) titre, absolute antibody titre (Abbott), T cell response (IFN-gamma) and epigenetics are analysed. Clinical data are collected. Patients are followed for up to 3 months beyond dose 5. Result(s): 105 children (64% haem, 36% solid cancers) and 399 adults (35% haem, 65% solid cancers) were enrolled. In adults, NAb response rate increased after dose 3 (Post 2: 40% haem, 87%solid;Post 3:70%haem,97%solid). Post dose 2, predictors of nonresponse were ChadOx1-S vaccine (OR 3 p = .02), haem cancer (OR 14 p < .001), ECOG >=1 (OR 2.6 p = .01) and steroids (OR 5 p = .01). Post dose 3, only haem cancer predicted non-response (OR 16). IFN-gamma response is available for a subset, detectable in 41/90 (46%) postdose 1, 78/96 (81%) post-dose 2 and 35/42 (83%) post-dose 3;without significant difference between haem and solid cancer. In children, NAb response post dose 2 is available for 50 patients. Response rate between haem (19/31, 61%) and solid patients (13/19, 68%) was similar. IFN-gamma response post dose 2 was also similar: (14/22, 63%) vs solid patients (12/14, 85%) (p = .25). Analysis is ongoing. Conclusion(s): Response to two doses of SARS-CoV-2 vaccine is suboptimal in patients with cancer. The third priming dose is integral, with significantly higher response rates observed. 36% of children did not develop neutralizing antibodies post dose 2;subsequent doses are likely to be important for young patients.
ABSTRACT
Background: COVID-19 infection has poor outcomes for patients (pts) with cancer. Understanding vaccine response as a correlate of protection from severe infection is essential to advise pts regarding protective behaviours and optimal vaccine schedule. This Australian cohort is unique due to low rates of COVID-19 exposure at study entry (July-November 2021). and use of a 3 dose schedule. Pts initially received 2 doses of either BNT162b2 (Pf) at a 3 week interval, or ChadOx1-S (AZ) at a 6 week interval, all then received a 3rd dose, either mRNA-1273 (Mod) or Pf after 2-4 months, and finally a 4th dose at an interval of a further 3 months, for a subset. Methods: SerOzNET (ACTRN12621001004853) has enrolled pts with solid and haematological (haem) cancers prior to initial vaccination. Serial blood samples were processed for serum, PBMC and PMN at timepoints: 0, then 3-4 weeks post dose 1 then 2 then 3 then 4 (where administered). We report here neutralizing antibodies (nAb) against wild type (wt) and delta and omicron variants of concern (VOC);quantitative S-protein IgG antibody (Abbott);Tcell correlates measured by levels of interferon-g (IFN g), tumour necrosis factor-a, interleukins (IL-) 2/ 4/5/13;and epigenetic profiling of T cells. Results: The cohort consists of 401 pts with median age 58 (range 18-85);59% female;128 (32%) haem cancers. 377 (94%) are on current or recent (< 12 months) systemic therapy: 162 (43%) chemotherapy, 62 (16%) immunotherapy, 40 (10%) combined chemo/immunotherapy, 113 (29%) hormonal or targeted therapy. 42 (10%) received anti-CD20 therapy < 12 months, 6 (1.4%) had allogeneic stem cell transplant. NAb levels against wt are available for 256 pts post dose 1, 245 pts post dose 2 and 159 pts post dose 3 (will be updated). Response rates post dose were respectively 27%, 77% and 88%. Pts with haem cancer were less likely to respond to vaccination at any time compared to pts with solid cancer (p < 0.001, chi-squared test). After 3 doses, 3.8% of pts with solid cancer and 27.8% with haem cancer lacked NAb. NAb results to VOC delta are available for 92 pts post dose 2: 25/92 (27%) were negative, compared with a non-response rate to wt of 15% at same time in same pts. IFN-γ-Spike response was detectable in 18/31 (58%) and 24/30 (80%) pts post dose 1 and 2 respectively. 101 pts to date have received a 4th dose;data will be available at the meeting, as will epigenetic profiles and detailed clinicopathological correlations. Conclusions: This interim analysis shows that a significant proportion of pts with haem cancers (27.8%) lack protective Sars-CoV-2 antibodies following 3 vaccinations, whereas only 3.8% of solid cancer pts lack detectable response. Results from other B and T cell parameters may also be important in identifying pts less well protected by vaccination. Follow up is ongoing, response rate post 4th dose will be presented at the meeting.
ABSTRACT
Background: Defining cancer and treatment-related factors which influence protection against COVID-19 following vaccination are important given the worse outcomes following infection in this group. Sophisticated and detailed studies which go beyond a single measure are required particularly with correlation to multiple disease and treatment factors. This study cohort is unique due to (a) very low prior COVID-19 infection at time of sampling (July-Nov 2021), (b) vaccines studied were BNT162b2 (Pf) given 3 weeks apart or ChAdOx1 (AZ) spaced 12 weeks (dose 1, 2) (c) most participants then received a third dose 2 months later (heterologous for AZ). Methods: SerOzNET (ACTRN12621001004853) enrols Australian blood and solid cancer patients prior to vaccination, with serial blood analyses and qualitative measures. We measured neutralizing antibodies (nAb) against SARS-CoV-2 wild type (wt) and variants of concern delta and omicron, quantitative S-protein IgG antibody level (Abbott), and T-cell correlates (interferon-g, tumour necrosis factor-a, interleukins 2/4/5/13) and epigenetic profiling at baseline and 3-4 weeks post dose 1, 2 +/- 3.Results: 379 participants were included, median age 58 years (IQR 47-66) and 60% female. 30% participants had hematological malignancies with the remainder solid organ cancers. 90% patients were on current systemic cancer treatment (most commonly chemotherapy in 41%, chemoimmunotherapy or immunotherapy in 20%). In 331 patients where treatment intent was recorded, 47% was palliative. Only one patient had known prior COVID-19 infection. Of the initial 94 participants who received Pf vaccination, median (IQR) neutralizing antibody titre 4 weeks following dose 2 was 80 (40-160) for SARS-CoV-2 wt and 40 (0-80) for delta variant. Conclusion: Neutralizing antibody titres in this Australian cancer population following Pf vaccination appear lower than those reported elsewhere such as CAPTURE study (Fendler et al, 2021), possibly related to shorter interdose interval. Preliminary data highlights low nAb titres as expected in haematology patients but also in some cases with treatment not traditionally associated with immunosuppression such as hormonal therapy. These results will be updated in February 2022 with third dose, AZ and omicron variant data.